Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2011 Sep 2.
Published in final edited form as: J Perinat Med. 2009;37(4):349–363. doi: 10.1515/JPM.2009.085

Maternal Serum Adiponectin Multimers in Preeclampsia

Shali Mazaki-Tovi 1,2, Roberto Romero 1,3,*, Edi Vaisbuch 1,2, Juan Pedro Kusanovic 1,2, Offer Erez 1,2, Francesca Gotsch 1, Tinnakorn Chaiworapongsa 1,2, Nandor Gabor Than 1, Sun Kwon Kim 1, Chia-Ling Nhan-Chang 1,2, Cristiano Jodicke 1,2, Percy Pacora 1, Lami Yeo 1,2, Zhong Dong 1, Bo Hyun Yoon 4, Sonia S Hassan 1,2, Pooja Mittal 1,2
PMCID: PMC3166229  NIHMSID: NIHMS304929  PMID: 19348608

Abstract

Objective

Obesity, insulin resistance, and dyslipidemia are associated with preeclampsia. Recently, “adipose tissue failure”, characterized by dysregulation of adipokine production, has been implicated in the pathophysiology of these metabolic complications. Adiponectin, an insulin-sensitizing, anti-atherogenic, anti-inflammatory and angiogenic adipokine, circulates in oligomeric complexes including: low-molecular-weight (LMW) trimers, medium-molecular-weight (MMW) hexamers and high-molecular-weight (HMW) isoforms. These multimers exert differential biological effects, and HMW to total adiponectin ratio (SA) has been reported to be a specific marker of adiponectin activity. The aim of this study was to determine whether preeclampsia is associated with changes in circulating adiponectin multimers.

Study design

This cross-sectional study included women with: 1) normal pregnancy (n=225); and 2) patients with mild preeclampsia (n=111). The study population was further stratified by first trimester BMI (normal weight <25 kg/m2 vs. overweight/obese ≥25 kg/m2). Serum adiponectin multimers (total, HMW, MMW and LMW) concentrations were determined by ELISA. Non-parametric statistics were used for analysis.

Results

1) The median maternal HMW and LMW adiponectin concentrations were lower in patients with preeclampsia than in those with normal pregnancies (p<0.001 and p=0.01, respectively); 2) patients with preeclampsia had a lower HMW/Total adiponectin ratio (p<0.001) and higher MMW/Total adiponectin and LMW/Total adiponectin ratios than those with a normal pregnancy (p<0.001 and p=0.009, respectively); 3) the presence of preeclampsia was independently associated with lower maternal serum HMW adiponectin concentrations (p=0.001) and with a low HMW/Total adiponectin ratio (p<0.001) after correction for maternal age, maternal BMI, the difference in BMI between the third and the first trimester, and gestational age at sampling; and 4) overweight/obese pregnant women had a lower median total and HMW adiponectin concentration than normal weight pregnant women among women with normal pregnancies, but not among those with preeclampsia.

Conclusion

1) Preeclampsia is associated with a lower median concentration of the HMW adiponectin isoform, the most active form of this adipokine, and a low HMW/Total adiponectin ratio, a specific marker of adiponectin biologic activity; 2) in contrast to normal pregnancy, preeclampsia is not associated with decreased circulating adiponectin multimers in overweight/obese individuals suggesting altered regulation of this adipokine in preeclampsia; 3) collectively, these findings suggest that preeclampsia is characterized by alterations in adiponectin multimers and their relative distribution implying a role for adiponectin multimers in the mechanism of disease in preeclampsia.

Keywords: Adipokines, Pregnancy, High-molecular-weight (HMW) adiponectin, Medium-molecular-weight (MMW) adiponectin, Low-molecular-weight (LMW) adiponectin, BMI, overweight, obesity

Introduction

Preeclampsia, one of the “great obstetrical syndromes”[139], is a leading cause of maternal and perinatal morbidity and mortality [35, 89, 150, 153]. Consistent with its syndromic nature, preeclampsia has been associated with an anti-angiogenic state [18, 23–25, 36, 39, 40, 49, 50, 78, 80, 85, 86, 90, 93, 98, 106, 140, 166, 181], endothelial cell dysfunction [28, 60, 77, 114, 129, 133, 147, 161], an exaggerated intravascular pro-inflammatory response [11, 22, 37, 47, 49, 53, 132, 143, 163] and a predominantly T helper (Th1)-biased immune response [30, 81, 108, 144, 158, 170]. In addition, preeclampsia has been associated with metabolic complications such as obesity, insulin resistance and dyslipidemia. This is of special importance, since the rising prevalence of metabolic complications is glaringly evident in women of reproductive age who are increasingly plagued by obesity[20] and because these metabolic alterations can be subjected to therapeutic manipulation by lifestyle modifications, medications or surgery.

A growing body of evidence strongly supports the association between preeclampsia and common metabolic complications: 1) obesity is an independent risk factor for preeclampsia [12, 20, 29, 38, 138, 152, 153, 174]; 2) patients with insulin resistance are more likely to develop preeclampsia [46, 64, 67, 69, 95, 141, 157, 176]; 3) preeclampsia is also associated with hypertriglyceridemia [51, 171], hypercholesterolemia [162], increased concentrations of free fatty acids [91] and reduced high density lipoprotein (HDL) concentrations [171]; and 4) women who had preeclampsia have an increased risk for metabolic syndrome-related morbidity [27, 48, 54, 154] and mortality [65, 68, 156] later in life. Despite the compelling evidence for the association between obesity-related complications and preeclampsia, the mechanism by which excess adipose tissue exerts its deleterious effect and predisposes pregnant women to develop preeclampsia remains unknown.

Adiponectin is the most abundant gene (AMP1) product of adipose tissue [62, 94, 110, 146] and it circulates at high concentrations in plasma[6, 62, 180]. Paradoxically, circulating concentrations of this adipokine are lower in obese than in non-obese subjects [8, 62], suggesting that an excess of adipose tissue can exert a negative feedback on adiponectin production or secretion. Adiponectin has been implicated in the pathophysiology of insulin resistance [14, 45, 55, 61, 175, 179], atherosclerosis [121, 123], hypertension [66, 72], dyslipidemia [97], and angiogenesis [124, 151]. These unique properties have prompted many investigators to explore the putative role of adiponectin in the physiologic metabolic adaptation during human pregnancy [21, 102, 107, 117], gestational diabetes mellitus (GDM) [73, 131, 177] and preeclampsia [31, 33, 58, 59, 70, 92, 113, 116, 130].

Adiponectin circulates in human plasma in distinct forms: 1) low-molecular-weight (LMW) trimers; 2) medium-molecular-weight (MMW) hexamers; and 3) high-molecular-weight (HMW) oligomers (12 to 18 subunits) [8, 126, 146, 168, 169, 172]. The significance of the various adiponectin multimers stems from the fact that each can exert differential biological effects [15, 75, 126, 169, 172]. Furthermore, several studies have highlighted the importance of the adiponectin sensitivity index (the ratio of HMW to total adiponectin - SA) [127] as a sensitive marker of its biological activity[9, 15, 44, 56, 71, 75, 109, 111, 127, 165]. Collectively these findings suggest that the physiological activity of adiponectin is primarily determined by the relative distribution of its isoforms.

Data regarding circulating maternal adiponectin multimers concentrations in human pregnancy are scarce [21, 42, 122, 134, 135, 160]. Indeed, only two studies reported the relative distribution of adiponectin isoforms in patients with preeclampsia [42, 160], of which only one [160] included all three isoforms in the analysis. Thus, the aim of this study was to determine whether there are changes in adiponectin multimers in normal and overweight/obese patients with preeclampsia.

Materials and methods

Study groups and inclusion criteria

A cross-sectional study was conducted including patients in the following groups: 1) normal pregnant women n=225); and 2) patients with mild preeclampsia (n=111). The study population was further stratified by first trimester body mass index (BMI: normal weight 18.5–24.9 kg/m2 vs. overweight/obese ≥25 kg/m2). Samples were taken immediately after the diagnosis of preeclampsia.

Samples and data were retrieved from our bank of biological samples and clinical databases. Many of these samples have previously been employed to study the biology of inflammation, hemostasis, angiogenesis regulation, and growth factor concentrations in normal pregnant women and those with pregnancy complications.

Written informed consent was obtained from all participants after approval by the Institutional Review Boards of the Sotero del Rio Hospital (Chile), Wayne State University (Detroit, Michigan, USA) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD; Bethesda, Maryland, USA).

Clinical Definitions

The inclusion criteria for normal pregnant women were: singleton gestation, no prior diabetes mellitus, no maternal or fetal complications during pregnancy, normal plasma glucose concentrations in the first trimester, normal oral glucose challenge test [3, 19], and delivery at term of a healthy neonate with a birthweight above the 10th percentile for gestational age [7].

Preeclampsia was defined as the presence of hypertension (systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg on at least two occasions, 4 hours to 1 week apart) and proteinuria (≥300 mg in a 24-hours urine collection or at least one dipstick measurement ≥2+) [1] .

The BMI was calculated according to the formula: weight (kg)/height (m2). Normal weight women were defined as those with a BMI of 18.5–24.9 kg/m2 according to the definition of the World Health Organization (WHO)[2] Pregnant women were classified by their first trimester BMI into two groups: normal weight and overweight/obese (BMI ≥25 kg/m2).

Sample collection and quantitative determination of multimeric forms of adiponectin in maternal serum

Maternal blood samples were collected with a vacutainer into tubes. Samples were centrifuged and the sera were stored at –80°C until analysis. Sensitive enzyme-linked immunoassays were used to determine the concentrations of adiponectin multimeric forms in maternal serum. Immunoassays were purchased from ALPCO Diagnostics (Salem, NH, USA). The assays were run according to the manufacturer’s recommendations. To detect HMW adiponectin, serum samples were pretreated with a specific protease that selectively digested MMW and LMW adiponectin. We were also able to determine the combined HMW and MMW adiponectin concentrations by pretreating the samples with a protease that specifically digested LMW adiponectin. Maternal serum samples were assayed directly to determine total adiponectin concentrations. Briefly, untreated and pretreated maternal serum samples were incubated in duplicate wells of the micro titer plates, which had been pre-coated with a monoclonal antibody specific for adiponectin. During this incubation any adiponectin present in the standards and untreated or pretreated maternal serum samples was bound by the immobilized antibodies. After repeated washing and aspiration to remove all unbound substances, an enzyme-linked polyclonal antibody specific for adiponectin was added to the wells. Unbound materials were removed with repeated washing and a substrate solution was added to the wells and color developed in proportion to the amount of adiponectin bound in the initial step. The color development was stopped with the addition of an acid solution and the intensity of color was read using a programmable spectrophotometer (SpectraMax M2, Molecular Devices, Sunnyvale, CA, USA). The concentration of adiponectin in untreated and treated maternal serum samples was determined by interpolation from individual standard curves composed of human adiponectin. Total, HMW, and HMW-MMW adiponectin concentrations were derived directly from the assay plates. MMW adiponectin concentrations were obtained by subtracting HMW adiponectin value from the combined HMW-MMW value. Finally, the LMW adiponectin value was computed by subtracting HMW and MMW adiponectin values from the total adiponectin values. The calculated inter- and intra-assay coefficients of variation for adiponectin multimers immunoassays in our laboratory were 2.2% and 4.2%, respectively. The sensitivity was calculated to be 0.04 ng/ml.

Statistical analysis

Normality of the data was tested using the Shapiro-Wilk and Kolmogorov-Smirnov tests. Since serum multimeric adiponectin isoforms concentrations were not normally distributed, Kruskal–Wallis tests with post-hoc analysis by Mann-Whitney U tests were used for comparisons of continuous variables. Comparison of proportions was performed by Chi-square or Fisher’s exact tests. Multiple linear regression analysis was performed to determine which factors were significantly and independently associated with maternal serum adiponectin isoforms concentrations as well as their relative distribution; due to skewed distribution logarithmic (log) transformation was employed in the latter analysis. The following parameters were included in the model: maternal age, maternal BMI (normal weight vs. overweight/obese), the difference in BMI between the third and the first trimesters, gestational age at sampling, and the presence of preeclampsia. A p-value <0.05 was considered statistically significant. Analysis was performed with SPSS, version 14 (SPSS Inc., Chicago, IL, USA).

Results

Table 1 displays the demographic and clinical characteristics of women with a normal pregnancy and those with preeclampsia. Patients with preeclampsia had a higher first and third trimester BMI and delivered smaller neonates. There were no significant differences in maternal age, parity, gestational age at blood sampling, gestational age at delivery and the third-to-first trimester BMI difference between patients with a normal pregnancy and those with preeclampsia (Table 1). Table 2 displays the demographic and clinical characteristics of the study population according to BMI. In both groups (normal pregnancy and preeclampsia) normal weight pregnant women were younger than overweight/obese patients. There were no significant differences in parity, gestational age at blood sampling, gestational age at delivery and neonatal birthweight between normal weight and overweight/obese women in both groups (Table 2).

Table 1.

Clinical and demographic characteristics of the study population

Normal Pregnancy
(n=225)		 Preeclampsia
(n=111)		 p
Maternal age (years) 32.8 (29.4–39.2) 36.8 (32.4–383) NS
Parity 1 (0–2) 2 (1–4) NS
First Trimester BMI (kg/m2) 23.5 (21.6–26.7) 29.1 (24.5–35.8) <0.001
Third Trimester BMI (kg/m2) 27.3 (25.0–32.4) 30.5 (24.5–42.7) <0.001
BMI difference between the third and first trimesters 5.6 (4.3–7.1) 5.8 (4.3–7.1) NS
Gestational age at blood sampling (weeks) 32.8 (29.4–39.2) 36.3 (32.4–38.3) NS
Gestational age at delivery (weeks) 39.9 (39.0–40.4) 37.0 (33.4–38.3) NS
Birth weight (g) 3460 (3220–3670) 2517 (1840–3142) <0.001
Open in a new tab

Values are expressed as median (interquartile range); NS- Not significant; BMI – Body Mass Index

Table 2.

Clinical and demographic characteristics of the study population according to body mass index

Normal Pregnancy Preeclampsia
Normal Weight
(n=141)		 Overweight/Obese
(n=84)		 p Normal Weight
(n=48)		 Overweight/Obese
(n=63)		 p
Maternal age (years) 25.0 (21.0–31.0) 29.0 (24.0–33.0) <0.01 21.0 (18.5–27.0) 26.0 (22.0–31.0) <0.01
Parity 1 (0–2) 1 (1–2) NS 2 (1–3) 2 (1–4) NS
First Trimester BMI
(kg/m2) 		22.2 (20.5–23.3) 27.2 (25.9–29.5) <0.01 22.8 (21.5–24.4) 32.4 (27.8–39.7) <0.01
Third Trimester BMI
(kg/m2) 		28.0 (26.3–29.6) 33.2 (30.4–35.4) <0.01 28.8 (26.7–30.7) 38.9 (34.2–45.9) <0.01
BMI difference 5.9 (4.8–7.3) 4.9 (3.5–5.8) <0.01 6.0 (4.7–7.2) 5.3 (4.0–7.7) NS
Gestational age at blood
sampling (weeks) 		33.0 (29.4–39.4) 32.8 (29.3–38.6) NS 33.2 (32.0–38.9) 37.0 (33.5–38.2) NS
Gestational age at
delivery (weeks) 		39.9 (39.2–40.3) 39.9 (38.9–40.7) NS 36.0 (32.7–39.0) 37.1 (34.0–38.2) NS
Birth weight (g) 3420 (3227–3660) 3510 (3220–3690) NS 2125 (1772–3095) 2625 (1895–3155) NS
Open in a new tab

Adiponectin multimers concentrations and their relative distribution in preeclampsia vs. normal pregnancy

The median maternal serum concentration of total adiponectin was lower in patients with preeclampsia than those with a normal pregnancy (median: 5,035 ng/mL, interquartile range [IQR] 3,329–6,979 vs. 6,415 ng/mL, IQR 4,651–8630; p<0.001, Figure 1). Similarly, patients with preeclampsia had a lower median serum concentrations of HMW (2,348 ng/mL, IQR 1,259–3,763 vs. 3619 ng/mL, IQR 2,252–5,142; p<0.001, Figure 1) and LMW adiponectin (1,084 ng/mL, IQR 812–1,493 vs. 1304 ng/mL, IQR 919–1,798; p=0.01, Figure 1) than those with a normal pregnancy. The median maternal serum concentration of MMW adiponectin did not differ between patients with preeclampsia and women with a normal pregnancy (1,386 ng/mL, IQR 892–1,789 vs. 1,427 ng/mL, IQR 1,010–1,902; p=0.7, Figure 1).

Figure 1. Comparison of the median serum total, HMW, MMW and LMW adiponectin concentrations between pregnant women with normal pregnancies and those with preeclampsia.

Figure 1

Open in a new tab

The median maternal serum concentration of total adiponectin was lower in patients with preeclampsia than in those with a normal pregnancy. Similarly, patients with preeclampsia had lower serum concentrations of HMW and LMW adiponectin than those with a normal pregnancy. The median maternal serum concentration of MMW adiponectin did not differ between patients with preeclampsia and those with a normal pregnancy (p=0.7).

The median maternal HMW/Total adiponectin ratio was lower in patients with preeclampsia than in those with a normal pregnancy (0.46, IQR 0.36–0.55 vs. 0.55, IQR 0.47–0.62; p<0.001, Figure 2). In contrast, patients with preeclampsia had a higher median MMW/Total adiponectin ratio (0.29, IQR 0.22–0.35 vs. 0.22, IQR 0.16–0.28; p<0.001, Figure 2) as well as a higher LMW/Total adiponectin ratio (0.25, IQR 0.17–0.31 vs. 0.21, IQR 0.15–0.28; p=0.009, Figure 2) than those with a normal pregnancy.

Figure 2. Comparison of HMW/Total adiponectin MMW/Total adiponectin and LMW/Total adiponectin ratios between pregnant women with normal pregnancies and those with preeclampsia.

Figure 2

Open in a new tab

The median maternal HMW/Total adiponectin ratio was lower in patients with preeclampsia than in those with a normal pregnancy. In contrast, patients with preeclampsia had a higher median MMW/Total adiponectin ratio as well as a higher LMW/Total adiponectin ratio than those with a normal pregnancy.

Adiponectin multimers concentrations and their relative distribution in preeclampsia: normal weight vs. overweight/obesity

Among patients with preeclampsia, women with normal weight and those with overweight/obesity did not differ in the median serum concentration of total adiponectin (4,010 ng/mL, IQR 2,968–6,748 vs. 5,228 ng/mL, IQR 3,378–6,810; p=0.3, Figure 3A), HMW adiponectin (1,434 ng/mL, IQR 1,130–3,659 vs. 2369 ng/mL, IQR 1,402–3,763; p=0.2, Figure 3B), MMW adiponectin (1,176 ng/mL, IQR 826–1,691 vs. 1,349 ng/mL, IQR 992–1,930; p=0.2, Figure 3C) and LMW adiponectin (1,031 ng/mL, IQR 787–1,484 vs. 1,096 ng/mL, IQR 777–1,493; p=0.98, Figure 3D).

Figure 3. Maternal serum total adiponectin (A), HMW adiponectin (B), MMW adiponectin (C) and LMW adiponectin (D) concentrations in women with a normal pregnancy and patients with preeclampsia according to first trimester BMI (normal weight vs. overweight/obese).

Figure 3

Figure 3

Figure 3

Figure 3

Open in a new tab

Among patients with preeclampsia, women of normal weight and those with overweight/obesity did not differ in the median serum concentration of total, HMW, MMW, and LMW adiponectin. Among patients with a normal weight, the median serum concentrations of total (A) and HMW (B) adiponectin were higher in women with a normal pregnancy than in those with preeclampsia. Among patients with overweight/obesity, the median serum concentrations of total (A) and HMW (B) adiponectin were higher in women with a normal pregnancy than in those with preeclampsia.

Similarly to women with a normal pregnancy, patients with preeclampsia with normal weight and those with overweight/obesity had a comparable median ratios of HMW/Total adiponectin (0.40, IQR 0.32–0.53 vs. 0.46, IQR 0.38–0.55; p=0.1, Figure 4A), MMW/Total adiponectin (0.29, IQR 0.22–0.37 vs. 0.28, IQR 0.21–0.35; p=0.9, Figure 4B), and LMW/Total adiponectin (0.25, IQR 0.21–0.39 vs. 0.15, IQR 0.15–0.30; p=0.2, Figure 4C).

Figure 4. Comparison of HMW/Total adiponectin (A) MMW/Total adiponectin (B) and LMW/Total adiponectin (C) ratios between pregnant women with a normal pregnancy and those with preeclampsia according to first trimester BMI (normal weight vs. overweight/obese).

Figure 4

Figure 4

Figure 4

Open in a new tab

Among patients with preeclampsia, patients with normal weight and those with overweight/obesity had a comparable median ratio of HMW/Total, MMW/Total, and LMW/Total adiponectin. Pregnant women with a normal pregnancy had a higher HMW/Total adiponectin ratio than those with preeclampsia (A). MMW/Total ratio (B) and LMW/Total adiponectin ratio (C) were lower in pregnant women with a normal pregnancy than in those with preeclampsia. Overweight/obese pregnant women with a normal pregnancy had a higher HMW/Total adiponectin ratio than those with preeclampsia (A). MMW/Total adiponectin ratio was lower in overweight/obese pregnant women with a normal pregnancy than in those with preeclampsia (B).

Adiponectin multimers concentrations and their relative distribution in normal weight pregnant women: normal pregnancy vs. preeclampsia

Among patients with a normal weight, women with a normal pregnancy had a higher median serum concentrations of total (7,025 ng/mL, IQR 5,235–3,763 vs. 4,010 ng/mL, IQR 2,968–6,748; p<0.001, Figure 3A), and HMW adiponectin (3,968 ng/mL, IQR 2,535–5,487 vs. 2,348 ng/mL, IQR 1,259–3,763; p<0.001, Figure 3B) than those with preeclampsia. There was no significant difference in the median maternal serum concentrations of MMW (1,446 ng/mL, IQR 1,010–1,970 vs. 1,176 ng/mL, IQR 826–1,691; p=0.08, Figure 3C) and LMW adiponectin (1,321 ng/mL, IQR 964–1,924 vs. 1,031 ng/mL, IQR 787–1,484; p=0.08, Figure 3D) between women with a normal pregnancy and those with preeclampsia.

Among normal weight women, those with a normal pregnancy had a higher HMW/Total adiponectin ratio than those with preeclampsia (0.56, IQR 0.48–0.63 vs. 0.40, IQR 0.32–0.53; p<0.001, Figure 4A). In contrast, MMW/Total (0.22, IQR 0.16–0.28 vs. 0.29, IQR 0.22–0.37; p=0.001, Figure 4B) and LMW/Total adiponectin ratios (0.20, IQR 0.15–0.28 vs. 0.25, IQR 0.21–0.39; p=0.004, Figure 4C) were lower in women with a normal pregnancy than in those with preeclampsia.

Adiponectin multimers concentrations and their relative distribution in overweight/obese women: normal pregnancy vs. preeclampsia

Among patients with overweight/obesity, women with a normal pregnancy had a higher median serum concentrations of total (5,370 ng/mL, IQR 4,464–5,142 vs. 5,228 ng/mL, IQR 3,378–6,810; p=0.03, Figure 3A) and HMW adiponectin (3,015 ng/mL, IQR 2,118–4,134 vs. 2369 ng/mL, IQR 1,402–3,763; p=0.01, Figure 3B) than those with preeclampsia. There was no significant difference in the median maternal serum concentrations of MMW adiponectin (1,403 ng/mL, IQR 973–1,762 vs. 1,349 ng/mL, IQR 992–1,930; p=0.7, Figure 3C) and LMW adiponectin (1,286 ng/mL, IQR 850–1,741 vs. 1,096 ng/mL, IQR 777–1,493; p=0.1, Figure 3D) between women with a normal pregnancy and those with preeclampsia.

Overweight/obese women with a normal pregnancy had a higher HMW/Total adiponectin ratio than those with preeclampsia (0.54, IQR 0.46–0.61 vs. 0.46, IQR 0.38–0.55; p=0.002, Figure 4A). In contrast, MMW/Total adiponectin ratio was lower in overweight/obese women with a normal pregnancy than in those with preeclampsia (0.22, IQR 0.17–0.28 vs. 0.28, IQR 0.21–0.35; p=0.002, Figure 4B). The median LMW/Total adiponectin ratio did not differ significantly between the two groups (0.22, IQR 0.15–0.28 vs. 0.15, IQR 0.15–0.30; p=0.3, Figure 4C).

Multivariable logistic regression analysis was used to examine the contribution of the presence of preeclampsia on the serum concentration of adiponectin isoforms, while adjusting for maternal age, maternal BMI (normal weight vs. overweight/obese), the difference in BMI between the third and the first trimester and gestational age at sampling. The final regression model suggested that the presence of preeclampsia was independently associated with decreased maternal serum HMW adiponectin concentrations (p=0.001) and HMW/Total adiponectin ratio (p<0.001), and with increased MMW/Total adiponectin ratio (p=0.007) and LMW/Total adiponectin ratio (p=0.006).

Discussion

Principal findings of the study

1) The median maternal HMW and LMW adiponectin concentrations were significantly lower in patients with preeclampsia than in those with normal pregnancies; 2) patients with preeclampsia had a significantly lower HMW/Total adiponectin ratio and a higher MMW/Total and LMW/Total adiponectin ratio than those with a normal pregnancy; 3) among patients with preeclampsia, neither maternal serum concentrations of adiponectin multimers, nor their relative distribution differ between normal weight and overweight/obese patients; and 4) the presence of preeclampsia was independently associated with low maternal serum HMW adiponectin concentration (p=0.001) and HMW/Total adiponectin ratio (p<0.001).

Adiponectin multimers: distinct structures, diverse actions

Adipocytes secrete adiponectin as multimeric complexes including: LMW trimers, MMW hexamers, and HMW oligomers (12–18 monomers) [126, 128, 168, 172, 173]. Of note, these multimeric forms cannot interchange with each other after secretion into the circulation [126]. This is pertinent, since distinct adiponectin isoforms have different biological actions. This evidence includes: 1) LMW adiponectin has an anti-inflammatory effect in vitro – monocytes and macrophages exposure to LMW adiponectin results in increased secretion of IL-10[115] and a decreased release of IL-6 [149]; 2) HMW and MMW adiponectin isoforms have pro-inflammatory properties in vitro – exposure of monocytes to HMW and MMW adiponectin results in increased secretion of IL-6[4] and IL-8 [142] chemokines; 3) only the HMW adiponectin isoform protects endothelial cells against apoptosis [75]; interestingly, the HMW, but not the LMW isoform, inhibits prostate cancer cell growth [17]; and 4) the different adiponectin multimers exert their action via activation of dissimilar signaling pathways, whereas LMW adiponectin activates AMP-activated protein kinase (AMPK) [169], and HMW as well as MMW activate NF-κB [57, 169].

Taken together, these reports support the notion that different adiponectin multimers have unique effects in the regulation of the metabolic and inflammatory pathways. These findings underline the significance of the relative distribution of adiponectin multimers as a method for the modulation of the diverse actions of this adipokine.

Alterations in adiponectin concentrations during gestation are associated with obesity-related pregnancy complications

The observations regarding the importance of various adipokines such as leptin [59, 74, 105, 107], C-reactive protein [107], tumor necrosis factor (TNF)-α [74, 107, 148], resistin [31, 58, 59, 82, 118], visfatin [26, 43, 52, 79, 88, 104] and specifically adiponectin [10, 31, 34, 99–103, 116, 117, 130, 131, 135, 167] in the regulation of metabolism and the inflammatory response, have been corroborated in human gestation.

Evidence in support of a role for adiponectin in normal gestation, preeclampsia and other pregnancy complications includes: 1) first trimester circulating adiponectin concentrations are significantly lower in pregnant women destined to develop preeclampsia than in those who will subsequently have gestational hypertension or a normal pregnancy [34]; 2) patients with previous preeclampsia have a lower adiponectin concentration (7–8 years after the index pregnancy) than those with a normal pregnancy [48]; 3) overweight pregnant patients have a lower adiponectin concentration than normal weight pregnant women;[117] and 4) pregnancy is associated not only with alterations in adiponectin concentrations [100, 102, 103, 155] but also with changes in the relative distribution of its multimers [21, 99, 134, 135].

Variation in circulating maternal concentration of adiponectin in patients with preeclampsia –evidence for the syndromic nature of preeclampsia?

The evidence concerning maternal adiponectin concentrations in the presence of preeclampsia is inconsistent: higher [41, 58, 59, 70, 92, 112, 113, 116, 130, 159], lower [31, 33, 34, 63, 125], and similar adiponectin concentrations [119, 120, 145, 160] have been reported in patients with preeclampsia compared to normal pregnant women. This alleged inconsistency may be due to differences in the study population characteristics, definitions of preeclampsia (mild vs. severe, early vs. late onset), sample size or methods by which adiponectin concentrations were determined. However, although it is possible to explain some of the discrepancies by differences in study design, the inconsistency of the results may reflect the syndromic nature of preeclampsia.

Altered function of adipose tissue is a feature of preeclampsia

The findings that the median maternal serum concentrations of HMW and LMW adiponectin are lower in patients with preeclampsia than in those with a normal pregnancy are novel. Prima facie, it seems that the decreased concentration of these isoforms in patients with preeclampsia merely reflects the reduction in total adiponectin concentrations in those patients. However, the lack of a significant change in MMW adiponectin, as well as the remarkable decrease in HMW adiponectin, suggest that additional mechanism(s) are involved in these changes. Moreover, the lower HMW/Total adiponectin ratio and the higher MMW/Total and LMW/Total adiponectin ratios, reported herein for the first time in patients with preeclampsia, suggest that the regulation of adiponectin production and/or secretion is altered in the presence of preeclampsia. Of interest, the various adiponectin isoforms cannot interchange with each other after secretion [126]. Thus, the altered regulation of adiponectin multimeric complexes occurs at the tissue level, specifically in the adipocytes. Collectively, the results of this study characterize altered function of adipose tissue as a feature of preeclampsia.

While there is ample literature regarding the changes in total adiponectin concentrations in patients with preeclampsia, data concerning the relative distribution of the different mulimeric complexes of this hormone are limited. Indeed, only two studies reported the relative distribution of adiponectin isoforms in patients with preeclampsia [42, 160]. Takemura et al.[160] described similar total adiponectin concentrations, but a higher maternal HMW adiponectin concentrations and an elevated HMW/Total adiponectin ratio in lean patients with preeclampsia (n=14) compared to lean normal pregnant women (n=14). Similarly, Fasshauer et al.[42] reported higher maternal serum HMW adiponectin concentrations in patients with preeclampsia (n=16) compared to lean normal pregnant women (n=20). The findings of the present study are in apparent contrast with the previous two reports. Several explanations for the alleged disparity in these findings can be hypothesized including differences in study population (specifically ethnicity, age) and clinical characteristics (i.e. higher prevalence of overweight/obesity in the present study), inclusion criteria for the control group and in the methods by which the adiponectin multimers were determined.

Why is preeclampsia associated with dysregulation of adiponectin multimeric complexes?

The decrease in HMW and LMW adiponectin and the significant dysregulation of its multimeric complexes in patients with preeclampsia reported herein are novel findings. The cross-sectional nature of the present study does not allow us to discern a cause-effect relationship between the changes in maternal serum adiponectin multimers and preeclampsia. However, several explanations for these intriguing results can be hypothesized:

1. Metabolic alterations in preeclampsia and functional implications of adiponectin multimeric abundance

HMW adiponectin is considered to be the most active form of adiponectin multimers. A growing body of evidence suggests that HMW adiponectin confers a protective metabolic effect: 1) the circulating concentration of HMW adiponectin has a superior correlation with several components of the metabolic syndrome (e.g. insulin resistance, dyslipidemia) over total adiponectin concentrations [83]; 2) increases in the HMW/Total adiponectin ratio, but not in the total adiponectin concentration, correlate with improved insulin sensitivity in patients with Type 2 diabetes mellitus (T2DM) treated with the thiazolidinediones (an insulin-sensitizing drug) [127]; and 3) a selective reduction in HMW adiponectin accounts for the decreased concentrations of total adiponectin in patients with T2DM [13] or obesity [75].

In the present study, both HMW and LMW adiponectin were lower in patients with preeclampsia than in those with a normal pregnancy. However, while the reduction in the absolute concentrations of HMW adiponectin resulted in a low HMW/Total adiponectin ratio in preeclampsia, the opposite was true for LMW/Total ratio. Thus, the decrease in total adiponectin concentration should be attributed primarily to reduced HMW adiponectin concentrations, suggesting that HMW adiponectin plays a role in the metabolic impairments associated with preeclampsia. Alternatively, the decreased concentrations and relative distribution of these multimeric complexes may be a reaction aimed to induce insulin resistance in order to allow decreased glucose utilization by maternal peripheral tissues to ensure increased availability of nutrients to the fetus. This may be of special importance in the presence of placental dysfunction, one of the hallmarks of preeclampsia.

2. Intravascular pro-inflammatory response, endothelial cell dysfunction and the changes in adiponectin isoforms

adiponectin has a potent anti-inflammatory action and an important regulatory effect on the integrity of the vasculature system. Preeclampsia is characterized by an exaggerated intravascular pro-inflammatory response [11, 22, 37, 47, 49, 53, 132, 143, 163] as well as by endothelial cell dysfunction[16, 28, 77, 114, 129, 133, 136, 137, 147, 161]. Hence, the decrease in adiponectin multimers in the presence of preeclampsia may point to a regulatory role for adiponectin in the pro-inflammatory response and endothelial cell dysfunction of preeclampsia. Noteworthy is that the concentration of LMW adiponectin, which has anti-inflammatory properties [149, 178], is reduced in patients with preeclampsia.

3. Adiponectin as a pro-angiogenic agent

adiponectin stimulates new blood vessel growth in vitro.[124] In accordance with this finding, adiponectin administration is required for angiogenesis in response to tissue ischemia in adiponectin knock-out mice [151]. Recently, a perturbation of angiogenesis has been implicated in the pathophysiology of preeclampsia. Indeed, both longitudinal and cross-sectional studies have characterized preeclampsia as an “anti-angiogenic state” [5, 18, 23–25, 32, 36, 39, 40, 49, 50, 76, 78, 80, 84–87, 90, 93, 98, 140, 164, 166]. In addition to its direct effect on angiogenesis, a recent study demonstrated a positive correlation between soluble Endoglin (sEng) and circulating adiponectin concentrations in patients with preeclampsia, but not in pregnant women with a normal pregnancy.[96] Similarly, a positive correlation between adiponectin and Soluble fms-like Tyrosine kinase 1 (sFlt-1) as well as a negative correlation with Placental Growth Factor (PlGF) in pregnant women with and without preeclampsia have been demonstrated [159]. Thus, low adiponectin concentrations may aggravate the endothelial dysfunction caused by alterations in angiogenesis in patients with preeclampsia.

In conclusion, it is tempting to postulate that the decrease in adiponectin multimers concentrations and the changes in their relative distribution results in a failure of this adipokine to exert its metabolic, inflammatory and angiogenic protective effects. This, in turn, may lead to the development or aggravation of the underlying mechanisms of disease implicated in preeclampsia.

Disparity between adiponectin multimers in normal and overweight/obese patients –evidence for altered regulation of adiponectin multimers production in preeclampsia

The results of the present study indicate that while the expected lower concentrations of total adiponectin and its multimers among women with normal pregnancies were documented in overweight/obese compared with normal weight patients with normal pregnancy [8, 99, 117], the decrement was blunted in overweight/obese patients with preeclampsia who had comparable concentrations of all adiponectin multimers to normal weight patients with preeclampsia. Interestingly, among both normal and overweight/obese patients, those with preeclampsia had lower concentrations of HMW, LMW and a low HMW/Total adiponectin ratio, suggesting that the alterations in maternal circulating adiponectin should be attributed primarily to the presence of preeclampsia.

Adiponectin is an exceptional adipokine since it is down-regulated in the presence of obesity. The results of this report underline preeclampsia as a condition in which the strong link between hypoadiponectinemia and obesity is disrupted. This finding further supports the notion of altered regulation of adiponectin multimers production by adipose tissue in preeclampsia.

In conclusion, adiponectin has been implicated in the pathophysiology of endothelial cell dysfunction, insulin resistance, inflammation, and anti-angiogenesis, all well recognized features of preeclampsia. Alterations in the relative distribution of adiponectin multimers are the result of regulation at the adipose tissue level and appear to determine the physiological effects of adiponectin. Comparing circulating adiponectin isoforms concentrations between normal weight and overweight/obese women with a normal pregnancy and those with preeclampsia reveals a distinct pattern of concentration and relative distribution of adiponectin multimers in patients with preeclampsia. Collectively the results of the present study suggest that dysregulation of adiponectin multimeric complexes are associated with preeclampsia and can provide a mechanistic molecular basis for the association between metabolic impairments, altered inflammatory response and preeclampsia.

Acknowledgment

Supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS.

Reference List

  • 1.ACOG practice bulletin. Diagnosis and management of preeclampsia and eclampsia. Number 33, January 2002. Obstet.Gynecol. 2002;99:159–167. doi: 10.1016/s0029-7844(01)01747-1. [DOI] [PubMed] [Google Scholar]
  • 2.World Health Organ Tech.Rep.Ser. Vol. 916. 2003. Diet, nutrition and the prevention of chronic diseases; p. i-149. backcover. [PubMed] [Google Scholar]
  • 3.ACOG Practice Bulletin. Clinical management guidelines for obstetrician-gynecologists. Number 30, September 2001 (replaces Technical Bulletin Number 200, December 1994). Gestational diabetes. Obstet.Gynecol. 2001;98:525–538. [PubMed] [Google Scholar]
  • 4.Abke S, Neumeier M, Weigert J, Wehrwein G, Eggenhofer E, Schaffler A, et al. Adiponectin-induced secretion of interleukin-6 (IL-6), monocyte chemotactic protein-1 (MCP-1, CCL2) and interleukin-8 (IL-8, CXCL8) is impaired in monocytes from patients with type I diabetes. Cardiovasc.Diabetol. 2006;5:17. doi: 10.1186/1475-2840-5-17. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Aggarwal PK, Jain V, Sakhuja V, Karumanchi SA, Jha V. Low urinary placental growth factor is a marker of pre-eclampsia. Kidney Int. 2006;69:621–624. doi: 10.1038/sj.ki.5000075. [DOI] [PubMed] [Google Scholar]
  • 6.Ahima RS, Flier JS. Adipose tissue as an endocrine organ. Trends Endocrinol.Metab. 2000;11:327–332. doi: 10.1016/s1043-2760(00)00301-5. [DOI] [PubMed] [Google Scholar]
  • 7.Alexander GR, Himes JH, Kaufman RB, Mor J, Kogan M. A United States national reference for fetal growth. Obstet.Gynecol. 1996;87:163–168. doi: 10.1016/0029-7844(95)00386-X. [DOI] [PubMed] [Google Scholar]
  • 8.Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, et al. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem.Biophys.Res.Commun. 1999;257:79–83. doi: 10.1006/bbrc.1999.0255. [DOI] [PubMed] [Google Scholar]
  • 9.Aso Y, Yamamoto R, Wakabayashi S, Uchida T, Takayanagi K, Takebayashi K, et al. Comparison of serum high-molecular weight (HMW) adiponectin with total adiponectin concentrations in type 2 diabetic patients with coronary artery disease using a novel enzyme-linked immunosorbent assay to detect HMW adiponectin. Diabetes. 2006;55:1954–1960. doi: 10.2337/db05-1525. [DOI] [PubMed] [Google Scholar]
  • 10.Ategbo JM, Grissa O, Yessoufou A, Hichami A, Dramane KL, Moutairou K, et al. Modulation of adipokines and cytokines in gestational diabetes and macrosomia. J.Clin.Endocrinol.Metab. 2006;91:4137–4143. doi: 10.1210/jc.2006-0980. [DOI] [PubMed] [Google Scholar]
  • 11.Barden A, Graham D, Beilin LJ, Ritchie J, Baker R, Walters BN, et al. Neutrophil CD11B expression and neutrophil activation in pre-eclampsia. Clin.Sci.(Lond) 1997;92:37–44. doi: 10.1042/cs0920037. [DOI] [PubMed] [Google Scholar]
  • 12.Barton JR, Sibai BM. Prediction and prevention of recurrent preeclampsia. Obstet.Gynecol. 2008;112:359–372. doi: 10.1097/AOG.0b013e3181801d56. [DOI] [PubMed] [Google Scholar]
  • 13.Basu R, Pajvani UB, Rizza RA, Scherer PE. Selective downregulation of the high molecular weight form of adiponectin in hyperinsulinemia and in type 2 diabetes: differential regulation from nondiabetic subjects. Diabetes. 2007;56:2174–2177. doi: 10.2337/db07-0185. [DOI] [PubMed] [Google Scholar]
  • 14.Berg AH, Combs TP, Du X, Brownlee M, Scherer PE. The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat.Med. 2001;7:947–953. doi: 10.1038/90992. [DOI] [PubMed] [Google Scholar]
  • 15.Bobbert T, Rochlitz H, Wegewitz U, Akpulat S, Mai K, Weickert MO, et al. Changes of adiponectin oligomer composition by moderate weight reduction. Diabetes. 2005;54:2712–2719. doi: 10.2337/diabetes.54.9.2712. [DOI] [PubMed] [Google Scholar]
  • 16.Bretelle F, Sabatier F, Blann A, D'Ercole C, Boutiere B, Mutin M, et al. Maternal endothelial soluble cell adhesion molecules with isolated small for gestational age fetuses: comparison with pre-eclampsia. BJOG. 2001;108:1277–1282. doi: 10.1111/j.1471-0528.2001.00259.x. [DOI] [PubMed] [Google Scholar]
  • 17.Bub JD, Miyazaki T, Iwamoto Y. Adiponectin as a growth inhibitor in prostate cancer cells. Biochem.Biophys.Res.Commun. 2006;340:1158–1166. doi: 10.1016/j.bbrc.2005.12.103. [DOI] [PubMed] [Google Scholar]
  • 18.Bujold E, Romero R, Chaiworapongsa T, Kim YM, Kim GJ, Kim MR, et al. Evidence supporting that the excess of the sVEGFR-1 concentration in maternal plasma in preeclampsia has a uterine origin. J.Matern.Fetal Neonatal Med. 2005;18:9–16. doi: 10.1080/14767050500202493. [DOI] [PubMed] [Google Scholar]
  • 19.Carpenter MW, Coustan DR. Criteria for screening tests for gestational diabetes. Am.J.Obstet.Gynecol. 1982;144:768–773. doi: 10.1016/0002-9378(82)90349-0. [DOI] [PubMed] [Google Scholar]
  • 20.Catalano PM. Management of obesity in pregnancy. Obstet.Gynecol. 2007;109:419–433. doi: 10.1097/01.AOG.0000253311.44696.85. [DOI] [PubMed] [Google Scholar]
  • 21.Catalano PM, Hoegh M, Minium J, Huston-Presley L, Bernard S, Kalhan S, et al. Adiponectin in human pregnancy: implications for regulation of glucose and lipid metabolism. Diabetologia. 2006;49:1677–1685. doi: 10.1007/s00125-006-0264-x. [DOI] [PubMed] [Google Scholar]
  • 22.Chaiworapongsa T, Gervasi MT, Refuerzo J, Espinoza J, Yoshimatsu J, Berman S, et al. Maternal lymphocyte subpopulations (CD45RA+ and CD45RO+) in preeclampsia. Am.J.Obstet.Gynecol. 2002;187:889–893. doi: 10.1067/mob.2002.127309. [DOI] [PubMed] [Google Scholar]
  • 23.Chaiworapongsa T, Romero R, Espinoza J, Bujold E, Mee KY, Goncalves LF, et al. Evidence supporting a role for blockade of the vascular endothelial growth factor system in the pathophysiology of preeclampsia. Young Investigator Award. Am.J Obstet Gynecol. 2004;190:1541–1547. doi: 10.1016/j.ajog.2004.03.043. [DOI] [PubMed] [Google Scholar]
  • 24.Chaiworapongsa T, Romero R, Gotsch F, Espinoza J, Nien JK, Goncalves L, et al. Low maternal concentrations of soluble vascular endothelial growth factor receptor-2 in preeclampsia and small for gestational age. J.Matern.Fetal Neonatal Med. 2008;21:41–52. doi: 10.1080/14767050701831397. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Chaiworapongsa T, Romero R, Kim YM, Kim GJ, Kim MR, Espinoza J, et al. Plasma soluble vascular endothelial growth factor receptor-1 concentration is elevated prior to the clinical diagnosis of pre-eclampsia. J Matern.Fetal Neonatal Med. 2005;17:3–18. doi: 10.1080/14767050400028816. [DOI] [PubMed] [Google Scholar]
  • 26.Chan TF, Chen YL, Lee CH, Chou FH, Wu LC, Jong SB, et al. Decreased plasma visfatin concentrations in women with gestational diabetes mellitus. J.Soc.Gynecol.Investig. 2006;13:364–367. doi: 10.1016/j.jsgi.2006.04.007. [DOI] [PubMed] [Google Scholar]
  • 27.Chesley SC, Annitto JE, Cosgrove RA. The remote prognosis of eclamptic women. Sixth periodic report. Am.J.Obstet.Gynecol. 1976;124:446–459. doi: 10.1016/0002-9378(76)90168-x. [DOI] [PubMed] [Google Scholar]
  • 28.Clark BA, Halvorson L, Sachs B, Epstein FH. Plasma endothelin levels in preeclampsia: elevation and correlation with uric acid levels and renal impairment. Am.J.Obstet.Gynecol. 1992;166:962–968. doi: 10.1016/0002-9378(92)91372-h. [DOI] [PubMed] [Google Scholar]
  • 29.Cnattingius S, Bergstrom R, Lipworth L, Kramer MS. Prepregnancy weight and the risk of adverse pregnancy outcomes. N.Engl.J.Med. 1998;338:147–152. doi: 10.1056/NEJM199801153380302. [DOI] [PubMed] [Google Scholar]
  • 30.Conrad KP, Miles TM, Benyo DF. Circulating levels of immunoreactive cytokines in women with preeclampsia. Am.J.Reprod.Immunol. 1998;40:102–111. doi: 10.1111/j.1600-0897.1998.tb00398.x. [DOI] [PubMed] [Google Scholar]
  • 31.Cortelazzi D, Corbetta S, Ronzoni S, Pelle F, Marconi A, Cozzi V, et al. Maternal and foetal resistin and adiponectin concentrations in normal and complicated pregnancies. Clin.Endocrinol.(Oxf) 2007;66:447–453. doi: 10.1111/j.1365-2265.2007.02761.x. [DOI] [PubMed] [Google Scholar]
  • 32.Crispi F, Dominguez C, Llurba E, Martin-Gallan P, Cabero L, Gratacos E. Placental angiogenic growth factors and uterine artery Doppler findings for characterization of different subsets in preeclampsia and in isolated intrauterine growth restriction. Am.J.Obstet.Gynecol. 2006;195:201–207. doi: 10.1016/j.ajog.2006.01.014. [DOI] [PubMed] [Google Scholar]
  • 33.D'Anna R, Baviera G, Corrado F, Giordano D, De VA, Nicocia G, et al. Adiponectin and insulin resistance in early- and late-onset pre-eclampsia. BJOG. 2006;113:1264–1269. doi: 10.1111/j.1471-0528.2006.01078.x. [DOI] [PubMed] [Google Scholar]
  • 34.D'Anna R, Baviera G, Corrado F, Giordano D, Di Benedetto A, Jasonni VM. Plasma adiponectin concentration in early pregnancy and subsequent risk of hypertensive disorders. Obstet.Gynecol. 2005;106:340–344. doi: 10.1097/01.AOG.0000168441.79050.03. [DOI] [PubMed] [Google Scholar]
  • 35.Dekker GA, Sibai BM. Etiology and pathogenesis of preeclampsia: current concepts. Am.J.Obstet.Gynecol. 1998;179:1359–1375. doi: 10.1016/s0002-9378(98)70160-7. [DOI] [PubMed] [Google Scholar]
  • 36.Erez O, Romero R, Espinoza J, Fu W, Todem D, Kusanovic JP, et al. The change in concentrations of angiogenic and anti-angiogenic factors in maternal plasma between the first and second trimesters in risk assessment for the subsequent development of preeclampsia and small-for-gestational age. J.Matern.Fetal Neonatal Med. 2008;21:279–287. doi: 10.1080/14767050802034545. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Erez O, Romero R, Kim SS, Kim JS, Kim YM, Wildman DE, et al. Over-expression of the thrombin receptor (PAR-1) in the placenta in preeclampsia: a mechanism for the intersection of coagulation and inflammation. J.Matern.Fetal Neonatal Med. 2008;21:345–355. doi: 10.1080/14767050802034859. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Eskenazi B, Fenster L, Sidney S. A multivariate analysis of risk factors for preeclampsia. JAMA. 1991;266:237–241. [PubMed] [Google Scholar]
  • 39.Espinoza J, Nien JK, Kusanovic JP, Goncalves LF, Medina LH, Gomez R, et al. The combined use of uterine artery Doppler and maternal plasma placental growth factor concentrations identifies patients at risk for early onset and/or severe preeclampsia. Ultrasound Obstet Gynecol. 2006;28:387–388. [Google Scholar]
  • 40.Espinoza J, Romero R, Nien JK, Kusanovic JP, Richani K, Gomez R, et al. A role of the anti-angiogenic factor sVEGFR-1 in the 'mirror syndrome' (Ballantyne's syndrome) J.Matern.Fetal Neonatal Med. 2006;19:607–613. doi: 10.1080/14767050600922677. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Fasshauer M, Seeger J, Waldeyer T, Schrey S, Ebert T, Lossner U, et al. Endogenous soluble receptor for advanced glycation endproducts is increased in preeclampsia. J.Hypertens. 2008;26:1824–1828. doi: 10.1097/HJH.0b013e3283060c5c. [DOI] [PubMed] [Google Scholar]
  • 42.Fasshauer M, Waldeyer T, Seeger J, Schrey S, Ebert T, Kratzsch J, et al. Circulating high-molecular-weight adiponectin is upregulated in preeclampsia and is related to insulin sensitivity and renal function. Eur.J.Endocrinol. 2008;158:197–201. doi: 10.1530/EJE-07-0454. [DOI] [PubMed] [Google Scholar]
  • 43.Fasshauer M, Waldeyer T, Seeger J, Schrey S, Ebert T, Kratzsch J, et al. Serum levels of the adipokine visfatin are increased in preeclampsia. Clin.Endocrinol.(Oxf) 2007 doi: 10.1111/j.1365-2265.2007.03147.x. [DOI] [PubMed] [Google Scholar]
  • 44.Fisher FF, Trujillo ME, Hanif W, Barnett AH, McTernan PG, Scherer PE, et al. Serum high molecular weight complex of adiponectin correlates better with glucose tolerance than total serum adiponectin in Indo-Asian males. Diabetologia. 2005;48:1084–1087. doi: 10.1007/s00125-005-1758-7. [DOI] [PubMed] [Google Scholar]
  • 45.Fruebis J, Tsao TS, Javorschi S, Ebbets-Reed D, Erickson MR, Yen FT, et al. Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice. Proc.Natl.Acad.Sci.U.S.A. 2001;98:2005–2010. doi: 10.1073/pnas.041591798. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Garner PR, D'Alton ME, Dudley DK, Huard P, Hardie M. Preeclampsia in diabetic pregnancies. Am.J.Obstet.Gynecol. 1990;163:505–508. doi: 10.1016/0002-9378(90)91184-e. [DOI] [PubMed] [Google Scholar]
  • 47.Gervasi MT, Chaiworapongsa T, Pacora P, Naccasha N, Yoon BH, Maymon E, et al. Phenotypic and metabolic characteristics of monocytes and granulocytes in preeclampsia. Am.J.Obstet.Gynecol. 2001;185:792–797. doi: 10.1067/mob.2001.117311. [DOI] [PubMed] [Google Scholar]
  • 48.Girouard J, Giguere Y, Moutquin JM, Forest JC. Previous hypertensive disease of pregnancy is associated with alterations of markers of insulin resistance. Hypertension. 2007;49:1056–1062. doi: 10.1161/HYPERTENSIONAHA.107.087528. [DOI] [PubMed] [Google Scholar]
  • 49.Gotsch F, Romero R, Friel L, Kusanovic JP, Espinoza J, Erez O, et al. CXCL10/IP-10: a missing link between inflammation and anti-angiogenesis in preeclampsia? J.Matern.Fetal Neonatal Med. 2007;20:777–792. doi: 10.1080/14767050701483298. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Gotsch F, Romero R, Kusanovic JP, Chaiworapongsa T, Dombrowski M, Erez O, et al. Preeclampsia and small-for-gestational age are associated with decreased concentrations of a factor involved in angiogenesis: soluble Tie-2. J.Matern.Fetal Neonatal Med. 2008;21:389–402. doi: 10.1080/14767050802046069. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51.Gratacos E, Casals E, Sanllehy C, Cararach V, Alonso PL, Fortuny A. Variation in lipid levels during pregnancy in women with different types of hypertension. Acta Obstet.Gynecol.Scand. 1996;75:896–901. doi: 10.3109/00016349609055024. [DOI] [PubMed] [Google Scholar]
  • 52.Haider DG, Handisurya A, Storka A, Vojtassakova E, Luger A, Pacini G, et al. Visfatin response to glucose is reduced in women with gestational diabetes mellitus. Diabetes Care. 2007;30:1889–1891. doi: 10.2337/dc07-0013. [DOI] [PubMed] [Google Scholar]
  • 53.Haller H, Ziegler EM, Homuth V, Drab M, Eichhorn J, Nagy Z, et al. Endothelial adhesion molecules and leukocyte integrins in preeclamptic patients. Hypertension. 1997;29:291–296. doi: 10.1161/01.hyp.29.1.291. [DOI] [PubMed] [Google Scholar]
  • 54.Hannaford P, Ferry S, Hirsch S. Cardiovascular sequelae of toxaemia of pregnancy. Heart. 1997;77:154–158. doi: 10.1136/hrt.77.2.154. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55.Hara K, Boutin P, Mori Y, Tobe K, Dina C, Yasuda K, et al. Genetic variation in the gene encoding adiponectin is associated with an increased risk of type 2 diabetes in the Japanese population. Diabetes. 2002;51:536–540. doi: 10.2337/diabetes.51.2.536. [DOI] [PubMed] [Google Scholar]
  • 56.Hara K, Horikoshi M, Yamauchi T, Yago H, Miyazaki O, Ebinuma H, et al. Measurement of the high-molecular weight form of adiponectin in plasma is useful for the prediction of insulin resistance and metabolic syndrome. Diabetes Care. 2006;29:1357–1362. doi: 10.2337/dc05-1801. [DOI] [PubMed] [Google Scholar]
  • 57.Haugen F, Drevon CA. Activation of nuclear factor-kappaB by high molecular weight and globular adiponectin. Endocrinology. 2007;148:5478–5486. doi: 10.1210/en.2007-0370. [DOI] [PubMed] [Google Scholar]
  • 58.Haugen F, Ranheim T, Harsem NK, Lips E, Staff AC, Drevon CA. Increased plasma levels of adipokines in preeclampsia: relationship to placenta and adipose tissue gene expression. Am.J.Physiol Endocrinol.Metab. 2006;290:E326–E333. doi: 10.1152/ajpendo.00020.2005. [DOI] [PubMed] [Google Scholar]
  • 59.Hendler I, Blackwell SC, Mehta SH, Whitty JE, Russell E, Sorokin Y, et al. The levels of leptin, adiponectin, and resistin in normal weight, overweight, and obese pregnant women with and without preeclampsia. Am.J.Obstet.Gynecol. 2005;193:979–983. doi: 10.1016/j.ajog.2005.06.041. [DOI] [PubMed] [Google Scholar]
  • 60.Higgins JR, Papayianni A, Brady HR, Darling MR, Walshe JJ. Circulating vascular cell adhesion molecule-1 in pre-eclampsia, gestational hypertension, and normal pregnancy: evidence of selective dysregulation of vascular cell adhesion molecule-1 homeostasis in pre-eclampsia. Am.J.Obstet.Gynecol. 1998;179:464–469. doi: 10.1016/s0002-9378(98)70380-1. [DOI] [PubMed] [Google Scholar]
  • 61.Hotta K, Funahashi T, Arita Y, Takahashi M, Matsuda M, Okamoto Y, et al. Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. Arterioscler.Thromb.Vasc.Biol. 2000;20:1595–1599. doi: 10.1161/01.atv.20.6.1595. [DOI] [PubMed] [Google Scholar]
  • 62.Hu E, Liang P, Spiegelman BM. AdipoQ is a novel adipose-specific gene dysregulated in obesity. J.Biol.Chem. 1996;271:10697–10703. doi: 10.1074/jbc.271.18.10697. [DOI] [PubMed] [Google Scholar]
  • 63.Ichida K, Moriyama T, Morita H, Kondo T, Yoshida S, Ohara N, et al. Plasma adiponectin concentrations and placental adiponectin expression in pre-eclamptic women. Gynecol.Endocrinol. 2007;23:238–243. doi: 10.1080/09513590701297740. [DOI] [PubMed] [Google Scholar]
  • 64.Innes KE, Wimsatt JH, McDuffie R. Relative glucose tolerance and subsequent development of hypertension in pregnancy. Obstet.Gynecol. 2001;97:905–910. doi: 10.1016/s0029-7844(01)01342-4. [DOI] [PubMed] [Google Scholar]
  • 65.Irgens HU, Reisaeter L, Irgens LM, Lie RT. Long term mortality of mothers and fathers after pre-eclampsia: population based cohort study. BMJ. 2001;323:1213–1217. doi: 10.1136/bmj.323.7323.1213. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 66.Iwashima Y, Katsuya T, Ishikawa K, Ouchi N, Ohishi M, Sugimoto K, et al. Hypoadiponectinemia is an independent risk factor for hypertension. Hypertension. 2004;43:1318–1323. doi: 10.1161/01.HYP.0000129281.03801.4b. [DOI] [PubMed] [Google Scholar]
  • 67.Joffe GM, Esterlitz JR, Levine RJ, Clemens JD, Ewell MG, Sibai BM, et al. The relationship between abnormal glucose tolerance and hypertensive disorders of pregnancy in healthy nulliparous women. Calcium for Preeclampsia Prevention (CPEP) Study Group. Am.J.Obstet.Gynecol. 1998;179:1032–1037. doi: 10.1016/s0002-9378(98)70210-8. [DOI] [PubMed] [Google Scholar]
  • 68.Jonsdottir LS, Arngrimsson R, Geirsson RT, Sigvaldason H, Sigfusson N. Death rates from ischemic heart disease in women with a history of hypertension in pregnancy. Acta Obstet.Gynecol.Scand. 1995;74:772–776. doi: 10.3109/00016349509021195. [DOI] [PubMed] [Google Scholar]
  • 69.Kaaja R, Laivuori H, Laakso M, Tikkanen MJ, Ylikorkala O. Evidence of a state of increased insulin resistance in preeclampsia. Metabolism. 1999;48:892–896. doi: 10.1016/s0026-0495(99)90225-1. [DOI] [PubMed] [Google Scholar]
  • 70.Kajantie E, Kaaja R, Ylikorkala O, Andersson S, Laivuori H. Adiponectin concentrations in maternal serum: elevated in preeclampsia but unrelated to insulin sensitivity. J.Soc.Gynecol.Investig. 2005;12:433–439. doi: 10.1016/j.jsgi.2005.04.006. [DOI] [PubMed] [Google Scholar]
  • 71.Katsuki A, Suematsu M, Gabazza EC, Murashima S, Nakatani K, Togashi K, et al. Decreased high-molecular weight adiponectin-to-total adiponectin ratio in sera is associated with insulin resistance in Japanese metabolically obese, normal-weight men with normal glucose tolerance. Diabetes Care. 2006;29:2327–2328. doi: 10.2337/dc06-1239. [DOI] [PubMed] [Google Scholar]
  • 72.Kazumi T, Kawaguchi A, Sakai K, Hirano T, Yoshino G. Young men with high-normal blood pressure have lower serum adiponectin, smaller LDL size, and higher elevated heart rate than those with optimal blood pressure. Diabetes Care. 2002;25:971–976. doi: 10.2337/diacare.25.6.971. [DOI] [PubMed] [Google Scholar]
  • 73.Kinalski M, Telejko B, Kuzmicki M, Kretowski A, Kinalska I. Tumor necrosis factor alpha system and plasma adiponectin concentration in women with gestational diabetes. Horm.Metab Res. 2005;37:450–454. doi: 10.1055/s-2005-870238. [DOI] [PubMed] [Google Scholar]
  • 74.Kirwan JP, Hauguel-De MS, Lepercq J, Challier JC, Huston-Presley L, Friedman JE, et al. TNF-alpha is a predictor of insulin resistance in human pregnancy. Diabetes. 2002;51:2207–2213. doi: 10.2337/diabetes.51.7.2207. [DOI] [PubMed] [Google Scholar]
  • 75.Kobayashi H, Ouchi N, Kihara S, Walsh K, Kumada M, Abe Y, et al. Selective suppression of endothelial cell apoptosis by the high molecular weight form of adiponectin. Circ.Res. 2004;94:e27–e31. doi: 10.1161/01.RES.0000119921.86460.37. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 76.Koga K, Osuga Y, Yoshino O, Hirota Y, Ruimeng X, Hirata T, et al. Elevated serum soluble vascular endothelial growth factor receptor 1 (sVEGFR-1) levels in women with preeclampsia. J Clin.Endocrinol.Metab. 2003;88:2348–2351. doi: 10.1210/jc.2002-021942. [DOI] [PubMed] [Google Scholar]
  • 77.Kraayenbrink AA, Dekker GA, van Kamp GJ, van Geijn HP. Endothelial vasoactive mediators in preeclampsia. Am.J.Obstet.Gynecol. 1993;169:160–165. doi: 10.1016/0002-9378(93)90154-b. [DOI] [PubMed] [Google Scholar]
  • 78.Krauss T, Pauer HU, Augustin HG. Prospective analysis of placenta growth factor (PlGF) concentrations in the plasma of women with normal pregnancy and pregnancies complicated by preeclampsia. Hypertens.Pregnancy. 2004;23:101–111. doi: 10.1081/PRG-120028286. [DOI] [PubMed] [Google Scholar]
  • 79.Krzyzanowska K, Krugluger W, Mittermayer F, Rahman R, Haider D, Shnawa N, et al. Increased visfatin concentrations in women with gestational diabetes mellitus. Clin.Sci.(Lond) 2006;110:605–609. doi: 10.1042/CS20050363. [DOI] [PubMed] [Google Scholar]
  • 80.Kupferminc MJ, Daniel Y, Englender T, Baram A, Many A, Jaffa AJ, et al. Vascular endothelial growth factor is increased in patients with preeclampsia. Am.J.Reprod.Immunol. 1997;38:302–306. doi: 10.1111/j.1600-0897.1997.tb00519.x. [DOI] [PubMed] [Google Scholar]
  • 81.Kusanovic JP, Romero R, Hassan SS, Gotsch F, Edwin S, Chaiworapongsa T, et al. Maternal serum soluble CD30 is increased in normal pregnancy, but decreased in preeclampsia and small for gestational age pregnancies. J.Matern.Fetal Neonatal Med. 2007;20:867–878. doi: 10.1080/14767050701482993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 82.Kusanovic JP, Romero R, Mazaki-Tovi S, Chaiworapongsa T, Mittal P, Gotsch F, et al. Resistin in amniotic fluid and its association with intra-amniotic infection and inflammation. J.Matern.Fetal Neonatal Med. 2008;21:902–916. doi: 10.1080/14767050802320357. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 83.Lara-Castro C, Luo N, Wallace P, Klein RL, Garvey WT. Adiponectin multimeric complexes and the metabolic syndrome trait cluster. Diabetes. 2006;55:249–259. [PubMed] [Google Scholar]
  • 84.Levine RJ, Lam C, Qian C, Yu KF, Maynard SE, Sachs BP, et al. Soluble endoglin and other circulating antiangiogenic factors in preeclampsia. N.Engl.J Med. 2006;355:992–1005. doi: 10.1056/NEJMoa055352. [DOI] [PubMed] [Google Scholar]
  • 85.Levine RJ, Maynard SE, Qian C, Lim KH, England LJ, Yu KF, et al. Circulating angiogenic factors and the risk of preeclampsia. N.Engl.J Med. 2004;350:672–683. doi: 10.1056/NEJMoa031884. [DOI] [PubMed] [Google Scholar]
  • 86.Levine RJ, Qian C, Maynard SE, Yu KF, Epstein FH, Karumanchi SA. Serum sFlt1 concentration during preeclampsia and mid trimester blood pressure in healthy nulliparous women. Am.J.Obstet.Gynecol. 2006;194:1034–1041. doi: 10.1016/j.ajog.2005.10.192. [DOI] [PubMed] [Google Scholar]
  • 87.Levine RJ, Thadhani R, Qian C, Lam C, Lim KH, Yu KF, et al. Urinary placental growth factor and risk of preeclampsia. JAMA. 2005;293:77–85. doi: 10.1001/jama.293.1.77. [DOI] [PubMed] [Google Scholar]
  • 88.Lewandowski KC, Stojanovic N, Press M, Tuck SM, Szosland K, Bienkiewicz M, et al. Elevated serum levels of visfatin in gestational diabetes: a comparative study across various degrees of glucose tolerance. Diabetologia. 2007;50:1033–1037. doi: 10.1007/s00125-007-0610-7. [DOI] [PubMed] [Google Scholar]
  • 89.Lindheimer MD. Hypertension in pregnancy. Hypertension. 1993;22:127–137. doi: 10.1161/01.hyp.22.1.127. [DOI] [PubMed] [Google Scholar]
  • 90.Lindheimer MD, Romero R. Emerging roles of antiangiogenic and angiogenic proteins in pathogenesis and prediction of preeclampsia. Hypertension. 2007;50:35–36. doi: 10.1161/HYPERTENSIONAHA.107.089045. [DOI] [PubMed] [Google Scholar]
  • 91.Lorentzen B, Drevon CA, Endresen MJ, Henriksen T. Fatty acid pattern of esterified and free fatty acids in sera of women with normal and pre-eclamptic pregnancy. Br.J.Obstet.Gynaecol. 1995;102:530–537. doi: 10.1111/j.1471-0528.1995.tb11355.x. [DOI] [PubMed] [Google Scholar]
  • 92.Lu D, Yang X, Wu Y, Wang H, Huang H, Dong M. Serum adiponectin, leptin and soluble leptin receptor in pre-eclampsia. Int.J.Gynaecol.Obstet. 2006 doi: 10.1016/j.ijgo.2006.06.015. [DOI] [PubMed] [Google Scholar]
  • 93.Lyall F, Greer IA, Boswell F, Fleming R. Suppression of serum vascular endothelial growth factor immunoreactivity in normal pregnancy and in pre-eclampsia. Br.J.Obstet.Gynaecol. 1997;104:223–228. doi: 10.1111/j.1471-0528.1997.tb11050.x. [DOI] [PubMed] [Google Scholar]
  • 94.Maeda K, Okubo K, Shimomura I, Funahashi T, Matsuzawa Y, Matsubara K. cDNA cloning and expression of a novel adipose specific collagen-like factor, apM1 (AdiPose Most abundant Gene transcript 1) Biochem.Biophys.Res.Commun. 1996;221:286–289. doi: 10.1006/bbrc.1996.0587. [DOI] [PubMed] [Google Scholar]
  • 95.Martinez AE, Gonzalez OM, Quinones GA, Ferrannini E. Hyperinsulinemia in glucose-tolerant women with preeclampsia. A controlled study. Am.J.Hypertens. 1996;9:610–614. doi: 10.1016/0895-7061(95)00448-3. [DOI] [PubMed] [Google Scholar]
  • 96.Masuyama H, Nakatsukasa H, Takamoto N, Hiramatsu Y. Correlation between soluble endoglin, vascular endothelial growth factor receptor −1 and adipocytokines in preeclampsia. J.Clin.Endocrinol.Metab. 2007 doi: 10.1210/jc.2006-2349. [DOI] [PubMed] [Google Scholar]
  • 97.Matsubara M, Maruoka S, Katayose S. Decreased plasma adiponectin concentrations in women with dyslipidemia. J.Clin.Endocrinol.Metab. 2002;87:2764–2769. doi: 10.1210/jcem.87.6.8550. [DOI] [PubMed] [Google Scholar]
  • 98.Maynard SE, Min JY, Merchan J, Lim KH, Li J, Mondal S, et al. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J.Clin.Invest. 2003;111:649–658. doi: 10.1172/JCI17189. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 99.Mazaki-Tovi S, Romero R, Kusanovic JP, Erez O, Vaisbuch E, Gotsch F, et al. Maternal Adiponectin Multimers In Normal Pregnancy. The Journal of Maternal-Fetal and Neonatal Medicine. 2008 doi: 10.1080/14767050802266881. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 100.Mazaki-Tovi S, Kanety H, Pariente C, Hemi R, Efraty Y, Schiff E, et al. Determining the source of fetal adiponectin. J.Reprod.Med. 2007;52:774–778. [PubMed] [Google Scholar]
  • 101.Mazaki-Tovi S, Kanety H, Pariente C, Hemi R, Schiff E, Sivan E. Cord blood adiponectin in large-for-gestational age newborns. Am.J.Obstet.Gynecol. 2005;193:1238–1242. doi: 10.1016/j.ajog.2005.05.049. [DOI] [PubMed] [Google Scholar]
  • 102.Mazaki-Tovi S, Kanety H, Pariente C, Hemi R, Wiser A, Schiff E, et al. Maternal serum adiponectin levels during human pregnancy. J.Perinatol. 2007;27:77–81. doi: 10.1038/sj.jp.7211639. [DOI] [PubMed] [Google Scholar]
  • 103.Mazaki-Tovi S, Kanety H, Sivan E. Adiponectin and human pregnancy. Curr.Diab.Rep. 2005;5:278–281. doi: 10.1007/s11892-005-0023-2. [DOI] [PubMed] [Google Scholar]
  • 104.Mazaki-Tovi S, Romero R, Kusanovic JP, Erez O, Gotsch F, Mittal P, et al. Visfatin/Pre-B cell colony-enhancing factor in amniotic fluid in normal pregnancy, spontaneous labor at term, preterm labor and prelabor rupture of membranes: an association with subclinical intrauterine infection in preterm parturition. J.Perinat.Med. 2008 doi: 10.1515/JPM.2008.084. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 105.McCarthy JF, Misra DN, Roberts JM. Maternal plasma leptin is increased in preeclampsia and positively correlates with fetal cord concentration. Am.J.Obstet.Gynecol. 1999;180:731–736. doi: 10.1016/s0002-9378(99)70280-2. [DOI] [PubMed] [Google Scholar]
  • 106.McKeeman GC, Ardill JE, Caldwell CM, Hunter AJ, McClure N. Soluble vascular endothelial growth factor receptor-1 (sFlt-1) is increased throughout gestation in patients who have preeclampsia develop. Am J Obstet Gynecol. 2004;191:1240–1246. doi: 10.1016/j.ajog.2004.03.004. [DOI] [PubMed] [Google Scholar]
  • 107.McLachlan KA, O'Neal D, Jenkins A, Alford FP. Do adiponectin, TNFalpha, leptin and CRP relate to insulin resistance in pregnancy? Studies in women with and without gestational diabetes, during and after pregnancy. Diabetes Metab Res.Rev. 2006;22:131–138. doi: 10.1002/dmrr.591. [DOI] [PubMed] [Google Scholar]
  • 108.Meekins JW, McLaughlin PJ, West DC, McFadyen IR, Johnson PM. Endothelial cell activation by tumour necrosis factor-alpha (TNF-alpha) and the development of pre-eclampsia. Clin.Exp.Immunol. 1994;98:110–114. doi: 10.1111/j.1365-2249.1994.tb06615.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 109.Modan-Moses D, Stein D, Pariente C, Yaroslavsky A, Ram A, Faigin M, et al. Modulation of adiponectin and leptin during refeeding of female anorexia nervosa patients. J.Clin.Endocrinol.Metab. 2007;92:1843–1847. doi: 10.1210/jc.2006-1683. [DOI] [PubMed] [Google Scholar]
  • 110.Nakano Y, Tobe T, Choi-Miura NH, Mazda T, Tomita M. Isolation and characterization of GBP28, a novel gelatin-binding protein purified from human plasma. J.Biochem.(Tokyo) 1996;120:803–812. doi: 10.1093/oxfordjournals.jbchem.a021483. [DOI] [PubMed] [Google Scholar]
  • 111.Nakashima R, Kamei N, Yamane K, Nakanishi S, Nakashima A, Kohno N. Decreased total and high molecular weight adiponectin are independent risk factors for the development of type 2 diabetes in Japanese-Americans. J.Clin.Endocrinol.Metab. 2006;91:3873–3877. doi: 10.1210/jc.2006-1158. [DOI] [PubMed] [Google Scholar]
  • 112.Nakatsukasa H, Masuyama H, Takamoto N, Hiramatsu Y. Circulating leptin and angiogenic factors in preeclampsia patients. Endocr.J. 2008;55:565–573. doi: 10.1507/endocrj.k07e-136. [DOI] [PubMed] [Google Scholar]
  • 113.Naruse K, Yamasaki M, Umekage H, Sado T, Sakamoto Y, Morikawa H. Peripheral blood concentrations of adiponectin, an adipocyte-specific plasma protein, in normal pregnancy and preeclampsia. J.Reprod.Immunol. 2005;65:65–75. doi: 10.1016/j.jri.2004.09.004. [DOI] [PubMed] [Google Scholar]
  • 114.Ness RB, Sibai BM. Shared and disparate components of the pathophysiologies of fetal growth restriction and preeclampsia. Am J Obstet Gynecol. 2006;195:40–49. doi: 10.1016/j.ajog.2005.07.049. [DOI] [PubMed] [Google Scholar]
  • 115.Neumeier M, Weigert J, Schaffler A, Wehrwein G, Muller-Ladner U, Scholmerich J, et al. Different effects of adiponectin isoforms in human monocytic cells. J.Leukoc.Biol. 2006;79:803–808. doi: 10.1189/jlb.0905521. [DOI] [PubMed] [Google Scholar]
  • 116.Nien JK, Mazaki-Tovi S, Romero R, Erez O, Kusanovic JP, Gotsch F, et al. Adiponectin in severe preeclampsia. J.Perinat.Med. 2007;35:503–512. doi: 10.1515/JPM.2007.121. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 117.Nien JK, Mazaki-Tovi S, Romero R, Erez O, Kusanovic JP, Gotsch F, et al. Plasma adiponectin concentrations in non-pregnant, normal and overweight pregnant women. J.Perinat.Med. 2007;35:522–531. doi: 10.1515/JPM.2007.123. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 118.Nien JK, Mazaki-Tovi S, Romero R, Kusanovic JP, Erez O, Gotsch F, et al. Resistin: a hormone which induces insulin resistance is increased in normal pregnancy. J.Perinat.Med. 2007;35:513–521. doi: 10.1515/JPM.2007.122. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 119.O'Sullivan AJ, Kriketos AD, Martin A, Brown MA. Serum adiponectin levels in normal and hypertensive pregnancy. Hypertens.Pregnancy. 2006;25:193–203. doi: 10.1080/10641950600912976. [DOI] [PubMed] [Google Scholar]
  • 120.Odden N, Henriksen T, Holter E, Grete SA, Tjade T, Morkrid L. Serum adiponectin concentration prior to clinical onset of preeclampsia. Hypertens.Pregnancy. 2006;25:129–142. doi: 10.1080/10641950600745475. [DOI] [PubMed] [Google Scholar]
  • 121.Okamoto Y, Kihara S, Ouchi N, Nishida M, Arita Y, Kumada M, et al. Adiponectin reduces atherosclerosis in apolipoprotein E-deficient mice. Circulation. 2002;106:2767–2770. doi: 10.1161/01.cir.0000042707.50032.19. [DOI] [PubMed] [Google Scholar]
  • 122.Ong GK, Hamilton JK, Sermer M, Connelly PW, Maguire G, Zinman B, et al. Maternal serum adiponectin and infant birthweight: the role of adiponectin isoform distribution. Clin.Endocrinol.(Oxf) 2007;67:108–114. doi: 10.1111/j.1365-2265.2007.02846.x. [DOI] [PubMed] [Google Scholar]
  • 123.Ouchi N, Kihara S, Arita Y, Maeda K, Kuriyama H, Okamoto Y, et al. Novel modulator for endothelial adhesion molecules: adipocyte-derived plasma protein adiponectin. Circulation. 1999;100:2473–2476. doi: 10.1161/01.cir.100.25.2473. [DOI] [PubMed] [Google Scholar]
  • 124.Ouchi N, Kobayashi H, Kihara S, Kumada M, Sato K, Inoue T, et al. Adiponectin stimulates angiogenesis by promoting cross-talk between AMP-activated protein kinase and Akt signaling in endothelial cells. J.Biol.Chem. 2004;279:1304–1309. doi: 10.1074/jbc.M310389200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 125.Ouyang Y, Chen H, Chen H. Reduced plasma adiponectin and elevated leptin in pre-eclampsia. Int.J.Gynaecol.Obstet. 2007;98:110–114. doi: 10.1016/j.ijgo.2007.04.021. [DOI] [PubMed] [Google Scholar]
  • 126.Pajvani UB, Du X, Combs TP, Berg AH, Rajala MW, Schulthess T, et al. Structure-function studies of the adipocyte-secreted hormone Acrp30/adiponectin. Implications fpr metabolic regulation and bioactivity. J.Biol.Chem. 2003;278:9073–9085. doi: 10.1074/jbc.M207198200. [DOI] [PubMed] [Google Scholar]
  • 127.Pajvani UB, Hawkins M, Combs TP, Rajala MW, Doebber T, Berger JP, et al. Complex distribution, not absolute amount of adiponectin, correlates with thiazolidinedione-mediated improvement in insulin sensitivity. J.Biol.Chem. 2004;279:12152–12162. doi: 10.1074/jbc.M311113200. [DOI] [PubMed] [Google Scholar]
  • 128.Phillips SA, Ciaraldi TP, Kong AP, Bandukwala R, Aroda V, Carter L, et al. Modulation of circulating and adipose tissue adiponectin levels by antidiabetic therapy. Diabetes. 2003;52:667–674. doi: 10.2337/diabetes.52.3.667. [DOI] [PubMed] [Google Scholar]
  • 129.Poston L, Chappell LC. Is oxidative stress involved in the aetiology of pre-eclampsia? Acta Paediatr.Suppl. 2001;90:3–5. doi: 10.1111/j.1651-2227.2001.tb01619.x. [DOI] [PubMed] [Google Scholar]
  • 130.Ramsay JE, Jamieson N, Greer IA, Sattar N. Paradoxical elevation in adiponectin concentrations in women with preeclampsia. Hypertension. 2003;42:891–894. doi: 10.1161/01.HYP.0000095981.92542.F6. [DOI] [PubMed] [Google Scholar]
  • 131.Ranheim T, Haugen F, Staff AC, Braekke K, Harsem NK, Drevon CA. Adiponectin is reduced in gestational diabetes mellitus in normal weight women. Acta Obstet.Gynecol.Scand. 2004;83:341–347. doi: 10.1111/j.0001-6349.2004.00413.x. [DOI] [PubMed] [Google Scholar]
  • 132.Redman CW, Sacks GP, Sargent IL. Preeclampsia: an excessive maternal inflammatory response to pregnancy. Am.J.Obstet.Gynecol. 1999;180:499–506. doi: 10.1016/s0002-9378(99)70239-5. [DOI] [PubMed] [Google Scholar]
  • 133.Redman CW, Sargent IL. Latest advances in understanding preeclampsia. Science. 2005;308:1592–1594. doi: 10.1126/science.1111726. [DOI] [PubMed] [Google Scholar]
  • 134.Retnakaran R, Connelly PW, Maguire G, Sermer M, Zinman B, Hanley AJ. Decreased high-molecular-weight adiponectin in gestational diabetes: implications for the pathophysiology of Type 2 diabetes. Diabet.Med. 2007;24:245–252. doi: 10.1111/j.1464-5491.2007.02077.x. [DOI] [PubMed] [Google Scholar]
  • 135.Retnakaran R, Hanley AJ, Connelly PW, Maguire G, Sermer M, Zinman B. Low serum levels of high-molecular weight adiponectin in Indo-Asian women during pregnancy: evidence of ethnic variation in adiponectin isoform distribution. Diabetes Care. 2006;29:1377–1379. doi: 10.2337/dc06-0413. [DOI] [PubMed] [Google Scholar]
  • 136.Roberts JM. Endothelial dysfunction in preeclampsia. Semin.Reprod.Endocrinol. 1998;16:5–15. doi: 10.1055/s-2007-1016248. [DOI] [PubMed] [Google Scholar]
  • 137.Roberts JM, Taylor RN, Musci TJ, Rodgers GM, Hubel CA, McLaughlin MK. Preeclampsia: an endothelial cell disorder. Am.J.Obstet.Gynecol. 1989;161:1200–1204. doi: 10.1016/0002-9378(89)90665-0. [DOI] [PubMed] [Google Scholar]
  • 138.Rode L, Nilas L, Wojdemann K, Tabor A. Obesity-related complications in Danish single cephalic term pregnancies. Obstet.Gynecol. 2005;105:537–542. doi: 10.1097/01.AOG.0000152304.39492.1c. [DOI] [PubMed] [Google Scholar]
  • 139.Romero R. The child is the father of the man. Prenat Neonat Med. 1996:8–11. [Google Scholar]
  • 140.Romero R, Nien JK, Espinoza J, Todem D, Fu W, Chung H, et al. A longitudinal study of angiogenic (placental growth factor) and anti-angiogenic (soluble endoglin and soluble vascular endothelial growth factor receptor-1) factors in normal pregnancy and patients destined to develop preeclampsia and deliver a small for gestational age neonate. J.Matern.Fetal Neonatal Med. 2008;21:9–23. doi: 10.1080/14767050701830480. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 141.Ros HS, Cnattingius S, Lipworth L. Comparison of risk factors for preeclampsia and gestational hypertension in a population-based cohort study. Am.J.Epidemiol. 1998;147:1062–1070. doi: 10.1093/oxfordjournals.aje.a009400. [DOI] [PubMed] [Google Scholar]
  • 142.Rovin BH, Song H. Chemokine induction by the adipocyte-derived cytokine adiponectin. Clin.Immunol. 2006;120:99–105. doi: 10.1016/j.clim.2006.01.010. [DOI] [PubMed] [Google Scholar]
  • 143.Sacks GP, Studena K, Sargent K, Redman CW. Normal pregnancy and preeclampsia both produce inflammatory changes in peripheral blood leukocytes akin to those of sepsis. Am.J.Obstet.Gynecol. 1998;179:80–86. doi: 10.1016/s0002-9378(98)70254-6. [DOI] [PubMed] [Google Scholar]
  • 144.Saito S, Umekage H, Sakamoto Y, Sakai M, Tanebe K, Sasaki Y, et al. Increased T-helper-1-type immunity and decreased T-helper-2-type immunity in patients with preeclampsia. Am.J.Reprod.Immunol. 1999;41:297–306. doi: 10.1111/j.1600-0897.1999.tb00442.x. [DOI] [PubMed] [Google Scholar]
  • 145.Savvidou MD, Sotiriadis A, Kaihura C, Nicolaides KH, Sattar N. Circulating levels of adiponectin and leptin at 23–25 weeks of pregnancy in women with impaired placentation and in those with established fetal growth restriction. Clin.Sci.(Lond) 2008;115:219–224. doi: 10.1042/CS20070409. [DOI] [PubMed] [Google Scholar]
  • 146.Scherer PE, Williams S, Fogliano M, Baldini G, Lodish HF. A novel serum protein similar to C1q, produced exclusively in adipocytes. J.Biol.Chem. 1995;270:26746–26749. doi: 10.1074/jbc.270.45.26746. [DOI] [PubMed] [Google Scholar]
  • 147.Schiff E, Ben-Baruch G, Peleg E, Rosenthal T, Alcalay M, Devir M, et al. Immunoreactive circulating endothelin-1 in normal and hypertensive pregnancies. Am.J.Obstet.Gynecol. 1992;166:624–628. doi: 10.1016/0002-9378(92)91688-7. [DOI] [PubMed] [Google Scholar]
  • 148.Schiff E, Friedman SA, Baumann P, Sibai BM, Romero R. Tumor necrosis factor-alpha in pregnancies associated with preeclampsia or small-for-gestational-age newborns. Am.J.Obstet.Gynecol. 1994;170:1224–1229. doi: 10.1016/s0002-9378(94)70130-x. [DOI] [PubMed] [Google Scholar]
  • 149.Schober F, Neumeier M, Weigert J, Wurm S, Wanninger J, Schaffler A, et al. Low molecular weight adiponectin negatively correlates with the waist circumference and monocytic IL-6 release. Biochem.Biophys.Res.Commun. 2007;361:968–973. doi: 10.1016/j.bbrc.2007.07.106. [DOI] [PubMed] [Google Scholar]
  • 150.Seely EW. Hypertension in pregnancy: a potential window into long-term cardiovascular risk in women. J.Clin.Endocrinol.Metab. 1999;84:1858–1861. doi: 10.1210/jcem.84.6.5785. [DOI] [PubMed] [Google Scholar]
  • 151.Shibata R, Ouchi N, Kihara S, Sato K, Funahashi T, Walsh K. Adiponectin stimulates angiogenesis in response to tissue ischemia through stimulation of amp-activated protein kinase signaling. J.Biol.Chem. 2004;279:28670–28674. doi: 10.1074/jbc.M402558200. [DOI] [PubMed] [Google Scholar]
  • 152.Sibai BM, Ewell M, Levine RJ, Klebanoff MA, Esterlitz J, Catalano PM, et al. Risk factors associated with preeclampsia in healthy nulliparous women. The Calcium for Preeclampsia Prevention (CPEP) Study Group. Am.J.Obstet.Gynecol. 1997;177:1003–1010. doi: 10.1016/s0002-9378(97)70004-8. [DOI] [PubMed] [Google Scholar]
  • 153.Sibai BM, Gordon T, Thom E, Caritis SN, Klebanoff M, McNellis D, et al. Risk factors for preeclampsia in healthy nulliparous women: a prospective multicenter study. The National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. Am.J.Obstet.Gynecol. 1995;172:642–648. doi: 10.1016/0002-9378(95)90586-3. [DOI] [PubMed] [Google Scholar]
  • 154.Sibai BM, Sarinoglu C, Mercer BM. Eclampsia. VII. Pregnancy outcome after eclampsia and long-term prognosis. Am.J.Obstet.Gynecol. 1992;166:1757–1761. doi: 10.1016/0002-9378(92)91566-s. [DOI] [PubMed] [Google Scholar]
  • 155.Sivan E, Mazaki-Tovi S, Pariente C, Efraty Y, Schiff E, Hemi R, et al. Adiponectin in human cord blood: relation to fetal birth weight and gender. J.Clin.Endocrinol.Metab. 2003;88:5656–5660. doi: 10.1210/jc.2003-031174. [DOI] [PubMed] [Google Scholar]
  • 156.Smith GC, Pell JP, Walsh D. Pregnancy complications and maternal risk of ischaemic heart disease: a retrospective cohort study of 129,290 births. Lancet. 2001;357:2002–2006. doi: 10.1016/S0140-6736(00)05112-6. [DOI] [PubMed] [Google Scholar]
  • 157.Solomon CG, Seely EW. Brief review: hypertension in pregnancy : a manifestation of the insulin resistance syndrome? Hypertension. 2001;37:232–239. doi: 10.1161/01.hyp.37.2.232. [DOI] [PubMed] [Google Scholar]
  • 158.Sunder-Plassmann G, Derfler K, Wagner L, Stockenhuber F, Endler M, Nowotny C, et al. Increased serum activity of interleukin-2 in patients with pre-eclampsia. J.Autoimmun. 1989;2:203–205. doi: 10.1016/0896-8411(89)90156-x. [DOI] [PubMed] [Google Scholar]
  • 159.Suwaki N, Masuyama H, Nakatsukasa H, Masumoto A, Sumida Y, Takamoto N, et al. Hypoadiponectinemia and circulating angiogenic factors in overweight patients complicated with pre-eclampsia. Am.J.Obstet.Gynecol. 2006 doi: 10.1016/j.ajog.2006.04.003. [DOI] [PubMed] [Google Scholar]
  • 160.Takemura Y, Osuga Y, Koga K, Tajima T, Hirota Y, Hirata T, et al. Selective increase in high molecular weight adiponectin concentration in serum of women with preeclampsia. J.Reprod.Immunol. 2007;73:60–65. doi: 10.1016/j.jri.2006.05.004. [DOI] [PubMed] [Google Scholar]
  • 161.Taylor RN, de Groot CJ, Cho YK, Lim KH. Circulating factors as markers and mediators of endothelial cell dysfunction in preeclampsia. Semin.Reprod.Endocrinol. 1998;16:17–31. doi: 10.1055/s-2007-1016249. [DOI] [PubMed] [Google Scholar]
  • 162.Thadhani R, Stampfer MJ, Hunter DJ, Manson JE, Solomon CG, Curhan GC. High body mass index and hypercholesterolemia: risk of hypertensive disorders of pregnancy. Obstet.Gynecol. 1999;94:543–550. doi: 10.1016/s0029-7844(99)00400-7. [DOI] [PubMed] [Google Scholar]
  • 163.Than NG, Romero R, Erez O, Kusanovic JP, Tarca AL, Edwin SS, et al. A Role for Mannose-Binding Lectin, a Component of the Innate Immune System in Pre-Eclampsia. Am.J.Reprod.Immunol. 2008 doi: 10.1111/j.1600-0897.2008.00631.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 164.Tidwell SC, Ho HN, Chiu WH, Torry RJ, Torry DS. Low maternal serum levels of placenta growth factor as an antecedent of clinical preeclampsia. Am.J.Obstet.Gynecol. 2001;184:1267–1272. doi: 10.1067/mob.2001.113129. [DOI] [PubMed] [Google Scholar]
  • 165.Tonelli J, Li W, Kishore P, Pajvani UB, Kwon E, Weaver C, et al. Mechanisms of early insulin-sensitizing effects of thiazolidinediones in type 2 diabetes. Diabetes. 2004;53:1621–1629. doi: 10.2337/diabetes.53.6.1621. [DOI] [PubMed] [Google Scholar]
  • 166.Torry DS, Wang HS, Wang TH, Caudle MR, Torry RJ. Preeclampsia is associated with reduced serum levels of placenta growth factor. Am J Obstet Gynecol. 1998;179:1539–1544. doi: 10.1016/s0002-9378(98)70021-3. [DOI] [PubMed] [Google Scholar]
  • 167.Tsai PJ, Yu CH, Hsu SP, Lee YH, Huang IT, Ho SC, et al. Maternal plasma adiponectin concentrations at 24 to 31 weeks of gestation: negative association with gestational diabetes mellitus. Nutrition. 2005;21:1095–1099. doi: 10.1016/j.nut.2005.03.008. [DOI] [PubMed] [Google Scholar]
  • 168.Tsao TS, Murrey HE, Hug C, Lee DH, Lodish HF. Oligomerization state-dependent activation of NF-kappa B signaling pathway by adipocyte complement-related protein of 30 kDa (Acrp30) J.Biol.Chem. 2002;277:29359–29362. doi: 10.1074/jbc.C200312200. [DOI] [PubMed] [Google Scholar]
  • 169.Tsao TS, Tomas E, Murrey HE, Hug C, Lee DH, Ruderman NB, et al. Role of disulfide bonds in Acrp30/adiponectin structure and signaling specificity. Different oligomers activate different signal transduction pathways. J.Biol.Chem. 2003;278:50810–50817. doi: 10.1074/jbc.M309469200. [DOI] [PubMed] [Google Scholar]
  • 170.Vince GS, Starkey PM, Austgulen R, Kwiatkowski D, Redman CW. Interleukin-6, tumour necrosis factor and soluble tumour necrosis factor receptors in women with pre-eclampsia. Br.J.Obstet.Gynaecol. 1995;102:20–25. doi: 10.1111/j.1471-0528.1995.tb09020.x. [DOI] [PubMed] [Google Scholar]
  • 171.Wakatsuki A, Ikenoue N, Okatani Y, Shinohara K, Fukaya T. Lipoprotein particles in preeclampsia: susceptibility to oxidative modification. Obstet.Gynecol. 2000;96:55–59. doi: 10.1016/s0029-7844(00)00858-9. [DOI] [PubMed] [Google Scholar]
  • 172.Waki H, Yamauchi T, Kamon J, Ito Y, Uchida S, Kita S, et al. Impaired multimerization of human adiponectin mutants associated with diabetes. Molecular structure and multimer formation of adiponectin. J.Biol.Chem. 2003;278:40352–40363. doi: 10.1074/jbc.M300365200. [DOI] [PubMed] [Google Scholar]
  • 173.Wang Y, Xu A, Knight C, Xu LY, Cooper GJ. Hydroxylation and glycosylation of the four conserved lysine residues in the collagenous domain of adiponectin. Potential role in the modulation of its insulin-sensitizing activity. J.Biol.Chem. 2002;277:19521–19529. doi: 10.1074/jbc.M200601200. [DOI] [PubMed] [Google Scholar]
  • 174.Weiss JL, Malone FD, Emig D, Ball RH, Nyberg DA, Comstock CH, et al. Obesity, obstetric complications and cesarean delivery rate--a population-based screening study. Am.J.Obstet.Gynecol. 2004;190:1091–1097. doi: 10.1016/j.ajog.2003.09.058. [DOI] [PubMed] [Google Scholar]
  • 175.Weyer C, Funahashi T, Tanaka S, Hotta K, Matsuzawa Y, Pratley RE, et al. Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J.Clin.Endocrinol.Metab. 2001;86:1930–1935. doi: 10.1210/jcem.86.5.7463. [DOI] [PubMed] [Google Scholar]
  • 176.Wolf M, Sandler L, Munoz K, Hsu K, Ecker JL, Thadhani R. First trimester insulin resistance and subsequent preeclampsia: a prospective study. J.Clin.Endocrinol.Metab. 2002;87:1563–1568. doi: 10.1210/jcem.87.4.8405. [DOI] [PubMed] [Google Scholar]
  • 177.Worda C, Leipold H, Gruber C, Kautzky-Willer A, Knofler M, Bancher-Todesca D. Decreased plasma adiponectin concentrations in women with gestational diabetes mellitus. Am.J.Obstet.Gynecol. 2004;191:2120–2124. doi: 10.1016/j.ajog.2004.04.038. [DOI] [PubMed] [Google Scholar]
  • 178.Wulster-Radcliffe MC, Ajuwon KM, Wang J, Christian JA, Spurlock ME. Adiponectin differentially regulates cytokines in porcine macrophages. Biochem.Biophys.Res.Commun. 2004;316:924–929. doi: 10.1016/j.bbrc.2004.02.130. [DOI] [PubMed] [Google Scholar]
  • 179.Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat.Med. 2001;7:941–946. doi: 10.1038/90984. [DOI] [PubMed] [Google Scholar]
  • 180.Yokota T, Oritani K, Takahashi I, Ishikawa J, Matsuyama A, Ouchi N, et al. Adiponectin, a new member of the family of soluble defense collagens, negatively regulates the growth of myelomonocytic progenitors and the functions of macrophages. Blood. 2000;96:1723–1732. [PubMed] [Google Scholar]
  • 181.Zhou Y, McMaster M, Woo K, Janatpour M, Perry J, Karpanen T, et al. Vascular endothelial growth factor ligands and receptors that regulate human cytotrophoblast survival are dysregulated in severe preeclampsia and hemolysis, elevated liver enzymes, and low platelets syndrome. Am.J.Pathol. 2002;160:1405–1423. doi: 10.1016/S0002-9440(10)62567-9. [DOI] [PMC free article] [PubMed] [Google Scholar]

RESOURCES