Abstract
Preeclampsia (PE), a hypertensive disorder of pregnancy, is increasing as a major contributor to perinatal and long-term morbidity of mother and offspring. PE is thought to originate from ischemic insults in the placenta driving the release of prohypertensive anti-angiogenic [soluble fms-like tyrosine kinase-1 (sFlt-1)] and proinflammatory [tumor necrosis factor-α (TNF-α)] factors into the maternal circulation. Whereas the increased incidence of PE is hypothesized to be largely due to the obesity pandemic, the mechanisms whereby obesity increases this risk are unknown. The maternal endothelium is targeted by placental and adipose tissue-derived factors like sFlt-1 and TNF-α that promote hypertension during pregnancy, resulting in vascular dysfunction and hypertension. Interestingly, not all obese pregnant women develop PE. Data suggest that obese pregnant women with the greatest metabolic abnormalities have the highest incidence of PE. Identifying obesity-related mechanisms driving hypertension in some obese pregnant women and pathways that protect normotensive obese pregnant women, may uncover novel protocols to treat PE. Metabolic abnormalities, such as increased circulating leptin, glucose, insulin, and lipids, are likely to increase the risk for PE in obese women. It is not only important to understand whether each of these metabolic factors contribute to the increased risk for PE in obesity, but also their cumulative effects. This is particularly relevant to obese pregnant women with gestational diabetes mellitus (GDM) where all of these factors are increased and the risk for PE is highest. It is speculated that these factors potentiate the anti-angiogenic and proinflammatory mechanisms of placental ischemia-induced vascular dysfunction thereby contributing to the increasing incidence of PE.
Keywords: adipose tissue, endothelium, gestational diabetes mellitus, hypertension, women’s health
proper placental and maternal vascular adaptations are important for healthy blood pressure regulation during pregnancy. Hypertensive disorders of pregnancy contribute to a large number of maternal and fetal deaths, not only in developing countries, but also nations like the United States (16). Preeclampsia (PE) is particularly dangerous, as it presents with new-onset hypertension ≥20 wk of gestation along with a number of systemic cardiovascular comorbidities, including endothelial and vascular dysfunction in the kidneys and the brain (3, 54). Human and experimental animal studies support that placental ischemia and hypoxia drive the release of antiangiogenic and proinflammatory factors from the placenta into the maternal circulation (93). There they promote endothelial and vascular dysfunction by reducing the bioavailability of the vasodilator nitric oxide (NO) and resulting in maternal hypertension.
The incidence of PE is on the rise and is thought to be a result of the obesity pandemic (71). A complete understanding of the impact of obesity and its associated metabolic abnormalities on the cascade of events leading from placental ischemia to maternal hypertension is not available. Reciprocally, not all obese pregnant women develop PE. This suggests that: 1) some obese pregnant women are protected against, whereas others are already predisposed to, vascular dysfunction and hypertension and that 2) obesity-related metabolic abnormalities and placental ischemia may be worse in obese preeclamptic patients. Understanding the differences between these two groups is likely to assist in our understanding of obesity’s impact on increasing the risk for developing preeclampsia.
Obesity is a Major Risk Factor for PE
Data overwhelmingly support that obesity is a major risk factor for hypertension during pregnancy (85). In a cohort of primiparous women from Pittsburgh, Pennsylvania having prepregnancy obesity, defined as a body mass index (BMI in kg/m2) >30, the incidence of PE was 14.5% and that of chronic hypertension with superimposed PE was 2.6% (96). These values were both higher than women with a prepregnancy BMI <30 (7.2% and 0.38%, respectively). Furthermore, the greater the degree of obesity, the greater was the incidence and severity for this maternal disorder.
Overweight, obese, and morbidly obese women are at respectively increased risk for developing PE with severe features at ≥34 wk of gestation (21). PE diagnosed at ≥34 wk of gestation is defined as late-onset PE. The American College of Obstetrics and Gynecology defines PE with severe features as new-onset severe hypertension with a systolic blood pressure of >160 mmHg or diastolic blood pressure >110 mmHg, or hypertension requiring antihypertensive therapy exclusive of chronic hypertension, which is concurrent with thrombocytopenia, impaired liver function, persistent right upper quadrant pain or epigastric pain, renal insufficiency, pulmonary edema, or central nervous system disturbances (3). Women with severe PE are more likely to be obese and have small for gestational-age babies (58), and obesity increases the need for inducing preterm birth (66). It may be that placental, adipose tissue, and underlying endothelial dysfunction mediate the impact of obesity on increasing the risk for PE.
Does Obesity Promote Morphological Abnormalities in Placental Vasculature?
Obesity and late-onset PE are associated with normal or larger fetal growth and birth weight with a placenta that is normal weight or even heavier (25, 49, 60). Such placental overgrowth in obesity is associated with fetal hypoxia (49). This increased placental weight may be related to “microvillous crowding” within a limited placental compartment (78). Therefore, the uterine capacity for villous expansion may become constrained at the end of pregnancy, which may be more pronounced in obese gravidas. It is known that the number of capillaries per villous tissue is increased in obesity (55). Future research should focus on the biophysics of uteroplacental constraint, its effects on the placental vascular tree, and the impact of obesity on this. Late PE, especially in obesity, then, may be a manifestation of “villous toxicity,” which is interesting because PE was once called toxemia of pregnancy.
Villous toxicity resulting from crowding and congestion likely cause cell death and hypoxia (78). Placental ischemia and hypoxia induces the release of prohypertensive factors including the proinflammatory cytokine tumor necrosis factor-α (TNF-α) and the anti-angiogenic factor soluble fms-like tyrosine kinase-1 (sFlt-1) from extravillous trophoblast cells. The latter binds and quenches bioavailable angiogenic and vasoprotective factors including vascular endothelial growth factor (VEGF) and placenta growth factor (PlGF), reducing activation of NO synthase (NOS). As the steepest fall in total peripheral vascular resistance and increase in plasma volume occurs late in healthy pregnancies, at ~8 mo of gestation (13, 40), late-onset PE may result from an underlying inability of the maternal cardiovascular system to properly vasodilate in response to placental-derived factors, like PlGF (1, 17, 57, 63, 75, 79), possibly mediated by synergistic actions of obesity-related metabolic factors and placental vascular dysfunction.
Do Maternal Obesity and Related Metabolic Factors Adversely Affect Uteroplacental-Fetal Vascular Function?
Obesity or high-fat diet adversely affect uteroplacental-fetal vascular remodeling and blood flow, which could lead to placental ischemia and hypoxia. In baboons segregated into obese and lean groups while on standard chow diet, the former had significantly greater perirenal fat and fasting venous circulating leptin levels; a slight increase in glucose; and no difference in insulin (24). In the placenta, these obese monkeys had reduced villous surface area but greater villous diameter. It is unclear if the reduced villous surface area was due to the metabolic abnormalities and/or greater numbers of macrophages found in the placental villous tissue and increased CD14 expression [a coreceptor for toll-like receptor (TLR)4 on macrophages] in maternal peripheral blood mononuclear cells and visceral adipose tissue. Blood pressure was not examined. Interestingly, greater numbers of proinflammatory macrophages are also found in placentas from obese pregnant women presenting with insulin resistance and increased leptin, IL-6, and C-reactive peptide along with greater CD68 and CD14 staining in placenta and TNF-α levels in placental macrophages (10).
In high-fat diet-induced obesity in pregnant mice, macrophage activation, but not total cell counts, and their cytokine levels were greater by the end of pregnancy. This was only observed in placentas from male fetuses, which fared worse (44, 67). This is interesting because higher levels of androgens promote insulin resistance in pregnant mice on high-fat diet (61), and inhibition of androgen signaling reduced systolic blood pressure, body fat, triglycerides, leptin, and increased adiponectin and improved glucose tolerance in this high-fat diet pregnant model (62). Placental and maternal vascular function was not examined. As a whole, these data support the need for studies designed to evaluate the combined importance of placental ischemia, sex hormones, obesity-related metabolic factors, and immune cells on blood pressure regulation in obese pregnancies.
Macrophages and T lymphocytes are activated in preeclamptic women (18, 23) and are more prevalent in obese placentas (49). Little is known regarding the role for macrophages in promoting hypertension during pregnancy. It has been shown that adoptive transfer of CD4+ T cells from lean rats with placental ischemia-induced hypertension (reduced uterine perfusion pressure, RUPP, model) elicited hypertension in once normotensive pregnant rats (92). It is unknown if obesity or obesity-related metabolic factors exaggerate the activation and prohypertensive actions of inflammatory cells in response to placental vascular dysfunction and ischemia. Indirect evidence suggests that the TLR4 receptor is a likely pathway whereby obesity could exaggerate these inflammatory mechanisms to increase risk for PE (81, 99). TLR4 is a novel receptor for high mobility group box 1 (HMGB1) (52). Hypoxic trophoblast cells release HMGB1 (43), and this factor is increased in placentas from preeclamptic pregnancies (11). Adipose tissue is also a source of circulating HMGB1, and it is suggested that its release is increased in obesity and insulin resistance, although this has only been studied in men (31). One study did find that circulating HMGB1 levels were greater in overweight pregnant women with gestational diabetes mellitus (GDM) (28). A clear role for this proinflammatory factor in mediating hypertension is not clear, as this cohort of women were only slightly overweight before pregnancy (BMI = 26.9 ± 2.0) vs. controls (BMI = 23.6 ± 2.37), and hypertensive patients were excluded. Placental blood flow was not examined.
Abnormal remodeling and widening of maternal spiral arteries during pregnancy is thought to be a major contributor to placental ischemia/hypoxia and the clinical manifestations of PE, at least the early-onset form. As a result, blood is forced through smaller distal spiral arteries, which would retain their muscular wall, resulting in increased flow turbulence, shear stress, and infarction in the intervillous space (45). Interestingly, endometrial and spiral artery blood flow is reduced in obese women before pregnancy (97). Furthermore, placentas from stillbirths of ≥20 wk of gestation having abnormal spiral artery modifications were associated with a greater incidence of maternal prepregnancy obesity and PE (4). These placentas also had acute atherosis, which is an atherosclerosis-like lesion typically found in the spiral arteries of women with PE (86). Shear stress may be a causative factor in the pathogenesis of such lesions, which could ultimately lead to thrombosis and placental infarcts. It is of utmost importance to understand the role of this in the pathogenesis of PE. This has begun to be examined utilizing atherosclerosis-prone ApoE−/− mice, which have hypertension and proteinuria during pregnancy compared with wild-type controls with greater edema and necrosis of the villous stroma, placental fat deposition and serum sFlt-1 levels (87). The contribution and timing of obesity and acute atherosis in altering placental vascular remodeling, and function and its role in inducing PE, should be determined.
Uteroplacental blood flow has been examined in nonhuman primates under high-fat diet conditions. Monkeys fed a high-fat diet for 4 yr segregated into obese-prone and obese-resistant groups. In the third trimester, the high-fat diet reduced uterine artery blood flow regardless of weight gain, but only reduced placental blood flow in the obese-prone group, as compared with the normal-diet group (26). It could be that those on the high-fat diet without significant weight gain had compensatory mechanisms to protect against placental ischemia, which was lost in those with high-fat diet-induced obesity and metabolic disease. Furthermore, placentas from the obese-prone group had increased infarction, calcification, and syncytial knotting, which are pathologies in ischemic placentas from preeclamptic women. While blood pressure was not examined in this study, there was increased TLR4, monocyte chemoattractant factor (MCP)-1, and interleukin (IL)-1β expression in the placenta. IL-1β has been shown to reduce endothelial NOS (19).
Is NOS/NO System a Target For Obesity-Related Metabolic Abnormalities to Promote Vascular Dysfunction in PE?
The dependency of maternal vascular function and blood pressure regulation on NOS/NO is increased during healthy pregnancy in humans and rodents (84). It has been suggested that NO is a target and reduced in obese hypertensive pregnancies. At delivery, in isolated chorionic plate arteries, there was reduced vasorelaxation response to the NO donor, sodium nitroprusside (SNP). There was no difference in the vasoconstriction response to the thromboxane analog U46619 in obese versus lean pregnant women (34) with uncomplicated pregnancies. At this point, it is not clear if this truly represents vascular dysfunction or an increase in endogenous NOS control of vascular tone, as it was not stated that the SNP responses were generated in the presence of NOS inhibition. This is important information because it has been shown using in vivo and ex vivo approaches that inhibition of NOS increases the response to SNP in isolated arteries (20), which implicates endogenous NOS in blunting the response to an exogenous NO donors. Therefore, it may be that endothelial function was actually increased, especially because they found that acute incubation with leptin at obese levels (100 ng/ml) attenuated U46619-induced vasoconstriction. Leptin blunts vasoconstriction via an endothelial NOS-dependent pathway and could be a potential mechanism whereby some obese pregnant women are protected and do not develop hypertension during pregnancy. It should be determined at which point increasing levels of leptin become vasoconstrictive and hypertensive, as we have found that leptin infusion and increasing circulating levels by five times in once normotensive rats elicited hypertension (69). Chorionic plate arteries from preeclamptic women are more vasoconstrictive (6). Whether underlying endothelial NOS dysfunction in the presence of placental ischemic factors mitigate the vasoprotective effects of leptin should be examined, as NOS inhibition is known to potentiate the prohypertensive actions of leptin (46).
In a separate study, using myometrial artery segments ≤500 µm in diameter isolated from obese pregnant women without pregnancy complications, there was blunted vasoconstriction to U46619 with no difference to arginine vasopressin (AVP). The response to bradykinin and SNP were blunted only in those arteries constricted with AVP, and this was prevented with indomethacin (33). It is not clear to what extent thromboxane and AVP control vascular tone in lean or obese normotensive and preeclamptic pregnancies and how this is regulated by the endothelium or NOS. It is known that during normal pregnancy that there is significantly reduced U46619 responsiveness, and therefore, is seemingly further lowered in uncomplicated obese pregnancies. It should be examined whether this is a compensatory mechanism to protect against placental ischemia in some obese pregnant women, as there are increased myeloperoxidase-producing (myeloperoxidase stimulates production of thromboxane) neutrophils around blood vessels in obese preeclamptic women, and this was positively correlated with blood pressure (80, 83). It is unclear how obesity and these mechanisms affect NOS.
There is evidence of fetoplacental vascular NOS dysfunction in a subset of women with supraphysiological gestational weight gain but having normal weight during before pregnancy (70). In umbilical vein rings, insulin-induced vasorelaxation was significantly impaired, which is suggestive of vascular insulin resistance. The authors proposed that this was due to reduced NOS signaling, as detected by its reduced expression in freshly isolated umbilical vein endothelial cells from these women, but this was not determined functionally in endothelial denudation or NOS inhibition experiments or in the kidney. It should be noted that these women did not have PE or any hypertensive disorder of pregnancy. Again, this suggests that compensatory mechanisms maintained blood pressure regulation. Interestingly, these women did not reach a level of metabolic dysfunction to present with altered oral glucose tolerance tests, suggesting that women may need to have obesity before pregnancy for the development of metabolic dysfunction during pregnancy. It may be necessary that obesity must be present along with underlying endothelial dysfunction for placental ischemic factors and/or obesity-related metabolic abnormalities to exaggerate vasoconstriction and vascular NOS dysfunction to cause hypertension in obese pregnancies. These characteristics, including reduced insulin-induced vasorelaxation, are found in GDM (94), which is thought to be mediated by increased proinflammatory TNF-α and IL-6 levels and altered adipokine levels with lower adiponectin and raised leptin levels (2).
Do Combined Obesity and Metabolic Abnormalities of GDM Promote Even Greater Risk For PE?
In the Hyperglycemia and Adverse Pregnancy Outcome Study (HAPO), a greater risk for PE was observed in obese pregnant women with GDM compared with either morbidity alone (8). Accumulating evidence supports that obesity increases the risk for PE by associating with GDM (12). Indeed, the increased incidence of preeclampsia accompanied by increases in BMI is generally accompanied by diabetes (32). Several studies have documented this risk (22, 37, 68, 89), with GDM even being an independent risk factor for PE (74).
Prepregnancy obesity holds more risk for gestational hypertension and GDM than net maternal gestational weight gain (36, 53). Circulating glucose levels are increased in obese pregnant women but are even greater in those obese pregnancies complicated by GDM (60). Increased fasting glycemia (>5.6 mmol/l) at the first prenatal visit predicted the development of GDM and PE in a Russian cohort (73). Therefore, it is likely that metabolic dysfunction may adversely affect placentation. In vitro studies showed that high glucose concentrations, mimicking those in GDM, inhibit extravillous trophoblast invasion (9). In vivo studies in monkeys emphasized that placental dysfunction in obesity occurred in association with maternal insulin resistance (42). The timing of this insulin resistance was not examined, but at the end of the study, these high-fat diet-fed, obese-prone pregnant monkeys were insulin resistant with elevated fasting insulin and leptin levels. They had reduced placental blood flow and increased placental inflammation. In humans, higher fasting and postload glucose levels were associated with higher cord-blood levels of insulin and leptin (48), but neither placental inflammation nor blood flow were examined. Indirect evidence suggests that uteroplacental blood flow is reduced in GDM, as insulin resistance attenuates the vasodilatory actions of adenosine in GDM in primary human umbilical vein endothelial cells (HUVECs) (94). Interestingly, in HUVECS from patients with GDM, insulin prevented the associated increased transport of l-arginine, which is a cofactor for NOS activity (30). It is unclear if this increased transport allowed uncoupled NOS to produce reactive oxygen species (ROS) with altered insulin signaling, potentially implicating vascular insulin resistance in fetoplacental vascular dysfunction. High-fat diet-fed mice with insulin resistance had increased placental hypoxia inducible factor (HIF)-1α, VEGF-A, and inflammation by the end of pregnancy (50). Eighty six percent of pregnant women with diabetes have some placental abnormality including villous immaturity, villous necrosis, chorangiosis, and increased angiogenesis (39, 42). GDM seems to promote placental ischemia/hypoxia, but its direct role in vascular dysfunction, inflammation, and blood pressure regulation is not known, especially as the circulating metabolic factors are so heterogeneous in this population (38).
To fully understand the role of obesity and metabolic abnormalities in the pathogenesis of PE, experimental animal studies are required to establish cause-and-effect relationships. Sprague-Dawley rats fed a high-fructose diet from the beginning of pregnancy presented with hyperglycemia and hypertension by the end of gestation (82). Induction of Type 1 diabetes mellitus by streptozotocin (STZ) in Wistar rats on gestational day 6 resulted in hypertension, as assessed by tail-cuff and proteinuria by gestational day 19 (41). Intriguingly, this was not found in a spontaneous model of Type 1 diabetes, the nonobese diabetic (NOD) mouse, where blood pressure and heart rate, assessed by telemetry, were reduced by the end of pregnancy but had albuminuria (7). Maternal overweight and obesity increased the risk for PE in patients with Type 1, not Type 2, diabetes (72). Perhaps the timing of obesity and hyperglycemia in pregnancy dictates whether it causes hypertension.
In a systematic review, it was concluded that insufficient glycemic control increased risk for PE (95). Whether hyperglycemia and insulin resistance have a synergistic role together with angiogenic imbalance to elicit exaggeration of hypertension during pregnancy is unknown. With the use of the surrogate marker of insulin sensitivity, sex hormone binding globulin (SHBG), it was found that women with the lowest levels of both SHBG and PlGF had the greatest risk for PE (90). Circulating PlGF levels are reduced in women with GDM (51).
Do Obesity-Related Metabolic Abnormalities Exaggerate Placental Ischemia-Induced Vascular Dysfunction and Hypertension?
Placental ischemia-induced hypertension has a strong dependency on angiogenic imbalance, and this may mediate obesity’s impact to increase the risk for PE. Indeed, PlGF levels are lower in obese versus lean PE patients with no difference in VEGF-A (77). In obese pregnancies examined at each gestational week, BMI was positively related to increased sFlt-1 over time, and the association of BMI versus time was significant in those with placental dysfunction, which was not directly compared with, but seemed greater than, normal pregnancy (98). In a cohort of obese women that went on to develop PE, PlGF levels at 20 to 22 wk of gestation were lower in overweight women compared with those that were underweight or normal weight and were even lower with obesity. These changes were associated with a much stronger correlation for PE in these heavier pregnant women (27). When more specifically examining diabetic preeclamptic pregnancies, those with combined PE and Type 2 diabetes had some of the lowest values of serum PlGF found (91). Moreover, there was a trend for lower cord serum PlGF in diabetic pregnancies with PE compared with those with any hypertensive disorder (56). Furthermore, sFlt-1 levels were increased with reduced PlGF in diabetic pregnancies complicated with PE over diabetic pregnancy alone, although a PE alone or obese groups were not included (14, 15).
It is apparent that prepregnancy obesity and metabolic abnormalities are linked to exaggerated reductions in angiogenic factors found in preeclamptic women. The cause for these reductions, and whether they contribute to the increased risk for PE in obese pregnancies, is unknown. As mentioned earlier, the ischemic placenta is active in promoting the hypertensive phenotype of PE. Placental ischemia and hypoxia-induced release of sFlt-1 quenches and reduces bioavailable proangiogenic and provasodilatory factors, notably VEGF and PlGF. Reduced angiogenic balance is mimicked by infusion of sFlt-1 into once normotensive pregnant rats whereby it drives up maternal blood pressure. Thus placental ischemia/hypoxia and subsequent production of sFlt-1 may be one source for altered angiogenic balance in obese, preeclamptic pregnancies. Interestingly, it is thought that adipose tissue may also contribute to the circulating pool of sFlt-1 (85). The integrative nature of placental ischemia and adipose tissue release of anti-angiogenic factors, for example, by soluble factors derived from the ischemic placenta driving adipose tissue to produce of prohypertensive factors, and vice versa, needs to be examined.
This has begun to be examined by utilizing omental adipose tissue explant cultures. There was no difference in the release of PlGF between pregnant women with preexisting obesity or lean controls with normal glucose tolerance or GDM, but PlGF levels were increased from those with combined obesity and GDM, with no difference in VEGF-A (47). This pattern was also found for sFlt-1 and soluble endoglin (sEng) and the proinflammatory marker soluble intercellular adhesion molecule-1 (sICAM-1). There was no difference for placental explant release of any of these factors between any of the groups, but it is important to note that those women with PE were excluded. Therefore, the interactions between placental ischemia-induced increases in circulating angiogenic imbalance; the ability of adipose tissue to release PlGF; and PlGF signaling in maternal blood vessels and adipose tissue should be examined. Reduced PlGF attenuates the gain of adipose tissue mass in response to high-fat diet during pregnancy in PlGF−/− mice. They were not able to compensate by increasing VEGF-A levels and also had an earlier rise in circulating leptin and hyperinsulinemia compared with wild-type controls (35). It is not known whether these changes are caused by reduced PlGF-mediated vascular dysfunction in the adipose tissue and other metabolic organs. Furthermore, blood pressure was not examined nor was endothelial function or the functional capacity of perivascular adipose tissue (PVAT) to regulate vascular tone examined in the face of reduced PlGF and increased obesity-related metabolic factors.
PVAT is a novel regulator of vasodilator tone with functional ability to buffer vasoconstriction. Adiponectin released from the PVAT induces vasodilation via NOS in human vessels (59), but it is reduced in obesity (29). In combined obesity and GDM, there are greater reductions in circulating adiponectin than obesity alone (76). The high molecular weight form is the only form reduced in PE (65) and GDM (64). High-fat diet-induced obese C57BL/6J mice had reduced circulating high molecular weight adiponectin, hyperinsulinemia and increased fetal weights during pregnancy and adiponectin infusion reversed these findings (5). Blood pressure, endothelial function, or PVAT buffering capacity was not examined.
Perspectives and Significance
The literature suggests that metabolic abnormalities are obligatory for obesity to increase the risk for PE. Understanding the pathogenesis of PE is an important women’s health issue. This is especially true as risk factors for this maternal disorder are increasing, such as prepregnancy obesity and metabolic disease. The individual and combined actions of prepregnancy obesity, high glucose, insulin, leptin, and reduced adiponectin may support the onset of PE by encouraging placental ischemia and exaggerating anti-angiogenic and inflammation-induced maternal vascular dysfunction. Figure 1 illustrates the hypothesis and integrative nature by which obesity and obesity-related metabolic factors reduce cytotrophoblast migration and reduced spiral artery remodeling and widening resulting in placental ischemia. It is also proposed that such obese conditions exaggerate placental ischemia-induced increases in circulating anti-angiogenic factors and proinflammatory pathways that collectively lead to reduced vascular NO levels, increased total peripheral resistance, and reduce renal excretory function culminating in the increased risk for PE in obese pregnancies. Interestingly, not all obese pregnant women develop PE, suggesting upregulation of vasoprotective mechanisms. Such protective pathways may be targeted in the face of obesity-induced GDM and metabolic disease to promote PE. Proper development of therapeutic strategies, such as treatment with PlGF or insulin-sensitizing drugs like metformin (88), may prove beneficial against PE and its long-term consequences. At this time point, the only steadfast treatment for PE is premature delivery of the baby and the ischemic placenta.
Fig. 1.
Hypothetical scheme with asterisks denoting where obesity and obesity-related abnormalities, such as increased leptin, glucose, insulin, and lipids, and gestational diabetes mellitus (GDM), may promote and even exaggerate the pathways linking placental ischemia to maternal hypertension.
GRANTS
This paper was funded by National Institute of General Medical Sciences (NIGMS) Grant P20GM104357 and National Heart, Lung, and Blood Institute (NHBLI) Grant K99HL130577.
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the author(s).
AUTHOR CONTRIBUTIONS
F.T.S. performed experiments; F.T.S. analyzed data; F.T.S. interpreted results of experiments; F.T.S. prepared figures; F.T.S. drafted manuscript; F.T.S. edited and revised manuscript; F.T.S. approved final version of manuscript.
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