Skip to main content
PMC home page
The Journal of Physiology logoLink to The Journal of Physiology
. 2006 Feb 9;572(Pt 1):51–58. doi: 10.1113/jphysiol.2005.104430

Evidence for altered placental blood flow and vascularity in compromised pregnancies

Lawrence P Reynolds 1, Joel S Caton 1, Dale A Redmer 1, Anna T Grazul-Bilska 1, Kimberly A Vonnahme 1, Pawel P Borowicz 1, Justin S Luther 1,2, Jacqueline M Wallace 2, Guoyao Wu 3, Thomas E Spencer 3
PMCID: PMC1779650  PMID: 16469783

Abstract

The placenta is the organ that transports nutrients, respiratory gases, and wastes between the maternal and fetal systems. Consequently, placental blood flow and vascular development are essential components of normal placental function and are critical to fetal growth and development. Normal fetal growth and development are important to ensure optimum health of offspring throughout their subsequent life course. In numerous sheep models of compromised pregnancy, in which fetal or placental growth, or both, are impaired, utero-placental blood flows are reduced. In the models that have been evaluated, placental vascular development also is altered. Recent studies found that treatments designed to increase placental blood flow can ‘rescue’ fetal growth that was reduced due to low maternal dietary intake. Placental blood flow and vascular development are thus potential therapeutic targets in compromised pregnancies.

‘During pregnancy the blood flow to the uterus increases to satisfy the metabolic demands of the conceptus.’Giacomo Meschia (1983)

The importance of the placental circulation to fetal growth has been recognized since ancient times. For example, in his great treatise, On the Generation of Animals (ca 340 B.C.), Aristotle stated:

‘The [umbilical] vessels join on the uterus like the roots of plants and through them the embryo receives its nourishment.’

In this brief review, we will evaluate the importance of the placental circulation to fetal growth and development, and then will attempt to answer the question, ‘Is placental vascular growth or function altered in compromised pregnancies?’ We will define compromised pregnancies broadly as those in which either fetal or placental growth, or both, are reduced. Once the evidence has been reviewed, we will ask the clinically relevant question, ‘Can placental blood flow or vascularity be used as a therapeutic target to ‘rescue’ fetal or placental growth in compromised pregnancies?’ Although we will concentrate on data in ruminants, for which there are numerous well-established models of compromised pregnancy, where applicable, data from other species will be discussed.

The importance of placental blood flow and vascularity to normal fetal growth and development

The placenta's primary role is to provide for physiological exchange between the fetal and maternal systems (Meschia, 1983; Reynolds & Redmer, 1995). In this context, the importance of the placental circulation to successful pregnancy is exemplified by the close relationships among fetal weight, placental size, and uterine and umbilical blood flows during normal pregnancies in many mammalian species (Reynolds et al. 2005a,b).

Uterine and umbilical blood flows, which primarily represent the circulation to the maternal and fetal portions of the placenta, respectively (Ramsey, 1982; Mossman, 1987), increase exponentially throughout gestation, essentially keeping pace with fetal growth (Reynolds & Redmer, 1995; Magness, 1998). For example, in sheep the absolute rate of uterine blood flow increases by approximately 3-fold (0.4–1.2 l min−1) throughout the last half of pregnancy (D 71–131, or 49–90% of gestation, respectively; Meschia, 1983). Over a similar interval of gestation, uterine blood of cows increases by 4.5-fold (2.9–13.2 l min−1; Reynolds et al. 1986) and that of humans increases by 2.5-fold (0.33–0.83 l min−1; Konje et al. 2003). The continual increase in the rate of uterine blood flow also seems to be the case for the other mammalian species (Meschia, 1983; Metcalfe et al. 1988; Reynolds & Redmer, 1995). Similarly, in sheep and cows, umbilical (fetal placental) blood flow increases dramatically throughout pregnancy, such that it keeps pace with fetal growth throughout the last half of gestation (Rudolph & Heymann, 1970; Bell et al. 1986; Reynolds et al. 1986; Reynolds & Ferrell, 1987; Molina et al. 1991). Although not measured directly, umbilical blood flow velocity increases and resistance decreases throughout the last half of gestation in humans (Gadelha Da Costa et al. 2005). Not only do absolute utero-placental flows increase throughout pregnancy, but importantly, the proportion of the total uterine and umbilical blood flows received by the caruncular and cotyledonary tissues, respectively, also increases as gestation progresses (Makowski et al. 1968a,b; Rosenfeld et al. 1974; Meschia, 1983).

Other critical placental functions such as the transport of oxygen and water also keep pace with fetal growth (Barcroft, 1946; Faber & Thornburg, 1983; Meschia, 1983; Reynolds & Redmer, 1995). As reported for umbilical blood flow, oxygen uptake and water transport remain constant when expressed per unit of fetal weight (Meschia, 1983; Reynolds et al. 1986; Reynolds & Ferrell, 1987). Similarly, fetal uptake of glucose essentially keeps pace with the rate of fetal growth (Reynolds et al. 1986; Molina et al. 1991).

Placental transport capacity may increase as gestation advances due to an increase in the rate of extraction of substances from uterine or umbilical blood (Barcroft, 1946; Faber & Thornburg, 1983; Meschia, 1983). In fact, extraction of oxygen per unit of uterine blood increases from mid- to late gestation in sheep and cattle (Meschia, 1983; Reynolds et al. 1986). Placental uptake is calculated based on the Fick principle:

graphic file with name tjp0572-0051-m1.jpg

where [A − V] represents the arterio-venous concentration difference. Thus, transplacental exchange could increase by increasing the rate of extraction (the A − V concentration difference) or by increasing the rate of blood flow, or both.

Based on numerous studies, it seems that increased blood flow is an important, if not the primary, mechanism of increased transplacental exchange throughout gestation (Meschia, 1983; Reynolds et al. 1986; Metcalfe et al. 1988; Ferrell, 1989). For example, in cattle oxygen extraction by the gravid uterus increases only 0.4-fold, whereas uterine blood flow increases approximately 4.5-fold from mid- to late gestation. Thus, increased uterine blood flow accounts for most of the 5- to 6-fold increase in total gravid uterine oxygen uptake. The 16-fold increase in oxygen uptake of the bovine fetus from mid- to late gestation also can be accounted for primarily by the increased rate of umbilical blood flow (Reynolds et al. 1986). Similarly in sheep, gravid uterine oxygen extraction increases approximately 0.4-fold from mid- to late gestation, whereas uterine blood flow increases approximately 3-fold (Meschia, 1983). Furthermore, the large increases in gravid uterine and fetal uptakes of glucose, lactate, and amino acid nitrogen from mid- to late gestation in cattle seem to depend primarily on large increases in uterine and umbilical blood flows because the arterio-venous concentration differences for these nutrients remain relatively constant (Reynolds et al. 1986; Reynolds & Redmer, 1995).

Thus, adequate blood flow to the placenta seems to be critical for normal fetal growth. At least for those substances that are diffusion limited, such as glucose, increased abundance of specific transporters and an increase in the maternal to fetal concentration gradient also seem to be important components of increased transplacental exchange (Bell et al. 1999). Nevertheless, gravid uterine and umbilical glucose uptakes, which provide for about 60% of fetal metabolic needs (Reynolds et al. 1986; Bell et al. 1999), are reduced approximately in proportion to the reduction in placental mass and blood flows in pregnancies compromised nutritionally or by environmental heat stress (Reynolds et al. 1985; Thureen et al. 1992; Wallace et al. 2002, 2005).

Based on the concept that chronic increases in blood flow to any growing tissue depend on vascular growth, or angiogenesis, Meschia (1983) reasoned that ‘the large increase of blood flow to the uterus during pregnancy … results primarily from the formation and growth of the placental vascular bed.’ In fact, numerous studies have indicated that angiogenesis is indeed a major component of the increase in placental blood flow throughout gestation, and establishment of functional fetal and placental circulations is one of the earliest events during embryonic/placental development (Reynolds & Redmer, 1995; Magness, 1998; Charnock-Jones et al. 2004; Kaufmann et al. 2004; Mayhew et al. 2004; Reynolds et al. 2005a,b).

Evidence that placental blood flow and vascularity are altered in compromised pregnancies

Since adequate blood flow to the placenta is critical for normal fetal growth, it is not surprising that conditions associated with reduced rates of fetal and placental growth (e.g. maternal or fetal genotype, increased numbers of fetuses, maternal nutrient deprivation or excess, environmental heat stress, high altitude) are associated with reduced rates of placental blood flow and reduced fetal oxygen and nutrient uptakes in numerous mammalian species, including humans (reviewed in Reynolds & Redmer, 1995; Poston, 1997; Mayhew et al. 2004; Reynolds et al. 2005a; Luther et al. 2005; Wallace et al. 2005). In fact, increased uterine vascular resistance and reduced uterine blood flow can be used as predictors of high-risk pregnancies and are associated with fetal growth retardation (Trudinger et al. 1985; North et al. 1994). Thus, the impact of factors that influence placental vascular development and function on fetal growth and development is striking (Reynolds & Redmer, 1995; Reynolds et al. 2005a). Moreover, observations in humans and livestock indicate that compromised fetal growth impacts not only the neonate but also health and productivity throughout life (Barker & Clark, 1997; Breier et al. 2001).

As summarized in Table 1, in sheep studied during late gestation, uterine or umbilical blood flows, or both, are reduced in every model of compromised pregnancy in which they have been evaluated. These models of compromised pregnancy include overfed adolescents, underfed adolescent and adult dams, as well as environmental heat stress, hypoxic stress, and multiple fetuses. These observations agree with those in women, in which placental perfusion is reduced in pregnancies with growth-restricted fetuses (Poston, 1997; Moore et al. 2004; Redmer et al. 2004b; Huppertz & Peeters, 2005).

Table 1.

Changes in fetal and placental weights, uterine and umbilical blood flows and placental vascularity in various models of compromised pregnancy in sheep

Model Day of gestation Fetal wt Placental wt Uterine blood flow Umbilical blood flow Vascularity Footnote
Overfed adolescent 130–134 ↓20–28% ↓45% ↓36% ↓37% ↓31% (total capillary vol.) 1
Underfed adolescent 130 ↓17% NSE* — — ↓20% (cap. area density, CAR) 2
Underfed adult 130–144 ↓12%   – ↓17–32% NSE ↓14% (cap. area density, CAR) 3
Adolescent versus adult 135 ↓11% ↓29% — — — 4
Genotype 130 ↓43% ↓47% — — ↑36% 5
Heat-stressed adult 133–135 ↓42% ↓51% ↓26% ↓60% — 6
Multiple pregnancy 140 ↓30% ↓37% ↓23% — ↓30% (total cap. vol., COT) 7
High dietary Se 135 NSE ↓24% — — ↑20% (cap number density, COT) 8
Hypoxic (hypobaric) stress 140 NSE — ↓35% — ↑ (cap. area density, CAR & COT) 9
Open in a new tab
1

Wallace et al. (2002); Redmer et al. (2004a). Uterine blood flow measured on day 130, fetal and placental weights on day 134 of gestation.

2

Luther et al. (2005). Although capillary area density (capillary area as a per cent of tissue area) was reduced by 20% (P < 0.001) in maternal caruncle, capillary number density (capillary number per unit tissue area) was increased by 23% (P < 0.09).

3

Chandler et al. (1985); Leury et al. (1990); Newnham et al. (1991); Kelly, 1992); Arnold et al. (2001). When nutrient restriction was severe (30–40% of full-fed controls) and during late pregnancy (day 120–144), uterine blood flow was reduced by 20–33%; when nutrient restriction was during mid-pregnancy, uterine blood flow was reduced by 17% or unaffected; in addition, capillary area density only tended (P < 0.09) to be reduced at day 130.

4

Borowicz et al. (2005a). Adolescents were peri-pubertal (approx. 7 months of age) and adults were approx. 1 year and 7 months of age; data are summarized for both Romanov (small-framed and small birth weight) and Columbia (large-framed and large birth weight) breeds.

5

Scheaffer et al. (2004); Borowicz et al. (2005a). Comparison for adult pregnancies in Romanov versus Columbia breeds. Although individual fetal weights were reduced by 43%, total fetal weight was similar or greater in Romanov versus Columbia ewes because of the larger number of fetuses in Romanovs. compared with Columbias (3–4 versus 1–2).

6

Regnault et al. (2003). Adult ewes were heat stressed from day 80–120 of gestation.

7

Data were expressed as per fetus for single- versus triplet-bearing ewes (fetal and placental weights, and placental vascularity; Grazul-Bilska et al. 2006), or for single- versus twin-bearing ewes (uterine blood flow; Christenson & Prior, 1978); all data were for adult ewes.

8

Borowicz et al. (2005b). High (but subtoxic) dietary Se was fed from day 50 of gestation until necropsy.

9

Krebs et al. (1997) and Parraguez et al. (2006) for vascularity data. Data for uterine blood flow are from humans at 36 weeks (90%) of gestation (Zamudio et al. 1995), as no data are available for sheep.

NSE, no significant effect.

In addition, although vascular development of the placenta also is decreased in several of the models of compromised pregnancy, it is increased in others (Table 1). Interestingly, in two of the models in which placental vascularity is increased (high dietary selenium or hypoxic stress; Table 1), there was no effect on fetal size, suggesting an adaptive placental response that preserves the fetal nutrient supply. In the other model exhibiting increased placental vascularity (Romanov versus Columbia genotype; Table 1), the animals were subject to long-term genetic selection resulting in increased litter size. This latter case resembles that of Meishan and Yorkshire pigs, in which the Meishans exhibit increased litter size and weight associated with increased placental vascularity and vascular endothelial growth factor (VEGF) expression (Biensen et al. 1998; Wilson et al. 1998; Vonnahme & Ford, 2004). Altered placental vascular development and expression of angiogenic factors in several of the sheep models of compromised pregnancy is similar to that reported in compromised pregnancies in humans, and Mayhew et al. (2004) suggested that most of these changes could be ‘driven’ by the relative fetal hypoxia. Nevetheless, alterations in fetal growth seem to be associated with altered placental vascular development, although the functional consequences of these alterations remain to be determined (Mayhew et al. 2004; Huppertz & Peeters, 2005; Reynolds et al. 2005a,b).

Altered placental growth and vascular development has been associated with altered expression of the genes for the major angiogenic factors, including VEGF, as well endothelial nitric oxide synthase (eNOS or NOS3), which produces nitric oxide (NO) and thus is an important regulator of both angiogenesis and vasodilatation (Reynolds & Redmer, 2001; Redmer et al. 2005; Reynolds et al. 2005a). Placental explants from pre-eclamptic human pregnancies exhibit increased production and release of soluble VEGF receptor-1, which binds to and inhibits the activity of VEGF ligands (Ahmad & Ahmed, 2005). Thus, placental angiogenic and vasoactive factors might serve as therapeutic targets in compromised pregnancies in humans (Godfrey, 2002; Ahmad & Ahmed, 2004).

Little data are available to address whether placental expression or production of vasoactive factors other than eNOS, or placental vasoactivity itself, is altered in compromised pregnancies. Vonnahme et al. (2004b) demonstrated a 2- to 4-fold increase in the placental vasoconstrictor response to a depolarizing dose of KCl when the dams were nutrient restricted during the first 40% of pregnancy, but not when they were subsequently re-fed and evaluated late in gestation. In fact, the placental vasoconstrictor response to angiotensin II was reduced in the re-fed dams, even though expression of angiotensin receptors 1 and 2 was similar to that of the control dams (Vonnahme et al. 2004a). These responses in vasoactivity are interesting because fetal growth was reduced during the nutrient restriction, in association with the increased placental vasoconstrictor response, whereas fetal size was normal in the re-fed dams late in gestation, when the placental vasoconstrictor response was blunted. In uterine arteries of rats in which placental perfusion is reduced experimentally, the vasoconstrictor response is enhanced, whereas endothelium-dependent vasorelaxation is reduced (Anderson et al. 2005). Interestingly, in humans the vasoconstrictor response of placental arteries to U46619, a thromboxane mimetic, was reduced in pregnancies exhibiting pre-eclampsia or intrauterine fetal growth restriction (Wareing & Baker, 2004). Thus, although the responses are complex, placental vasoactivity seems to be altered, and vasoactive factors are therefore logical therapeutic targets in compromised pregnancies.

Potential of placental blood flow and vascularity as therapeutic targets

Fetal growth restriction, resulting in low birth weight, occurs in 7–8% of human pregnancies in the United States, and is associated with increased perinatal mortality and morbidity (NLM, 2002a,b; NVSR, 2004). Because of the importance of placental blood flow to placental function, and the recognition that placental size, utero-placental blood flows, and expression of angiogenic and vasoactive factors are reduced or altered in compromised pregnancies, it has been suggested that therapeutic agents that target placental blood flow might be used to ameliorate fetal growth restriction (Godfrey, 2002; Ahmad & Ahmed, 2004; Wu et al. 2004; Wareing et al. 2005).

As discussed in the following paragraphs, perhaps some of the best candidates are the phosphodiesterase 5 (PDE5A)-specific inhibitors, which include sildenafil, tadalafil and vardenafil (marketed under the trade names Viagra, Cialis and Levitra, respectively). These pharmacological agents enhance the vasodilatory action of NO by inhibiting the breakdown of cGMP, the second messenger for NO, thus causing sustained relaxation of vascular smooth muscle (Michel, 2006).

Nitric oxide is an important regulator of blood flow to the uterus in the non-pregnant state and also during pregnancy (Magness, 1998). Expression of both eNOS and soluble guanylate cyclase, which serves as the receptor for NO and thus mediates its effects in vascular smooth muscle, are elevated in uterine arteries during pregnancy (Itoh et al. 1998; Vagnoni et al. 1998; Zheng et al. 2000; Magness et al. 2001; Joyce et al. 2002). In addition, basal production of NO contributes to low feto-placental vascular resistance during pregnancy (Sladek et al. 1997). Circulating NO and its metabolites are elevated in pregnancies with multiple compared with single fetuses (Vonnahme et al. 2005). As mentioned previously, placental expression of eNOS was reduced in some models of compromised pregnancy, including various conditions associated with intrauterine growth restriction in humans (Bird et al. 2003; Maul et al. 2003; Wu et al. 2004; Redmer et al. 2005). Moreover, NO, produced by endothelial cells, and VEGF, produced primarily by vascular smooth muscle and capillary pericytes, may interact by stimulating each other's expression (Ahmed & Perkins, 2000; Reynolds & Redmer, 2001). Thus, impaired placental syntheses of NO may provide a unified explanation for fetal growth retardation in both underfed and overfed sheep models of fetal growth restriction (Wu et al. 2004).

Oestrogens are probably important mediators of utero-placental blood flow and vascularity changes observed during pregnancy (Magness, 1998). Oestrogen treatment of ovariectomized ewes increases uterine blood flow and eNOS expression (Vagnoni et al. 1998; Rupnow et al. 2001). Sildenafil enhanced both basal and oestrogen-induced increases in uterine blood flow in ovariectomized ewes (Zoma et al. 2004). Wareing et al. (2005) found enhanced vasoconstrictor and reduced vasodilator responses of myometrial arteries from growth-restricted pregnancies; in the same study, sildenafil citrate significantly reduced vasoconstriction and significantly improved vasorelaxation. In a recent, and very preliminary, study (M. C. Satterfield, G. Wu & T.E. Spencer, unpublished results), we found that sildenafil administered subcutaneously from day 28 to day 112 of gestation significantly improved fetal weights in compromised pregnancies in ewes, using the maternal undernutrition model described by Vonnahme et al. (2003). Thus, the available data in humans and sheep support the suggestion that PDE5A inhibitors may offer a potential therapeutic tool to improve utero-placental blood flow in compromised pregnancies.

In addition, nutriceutical approaches may also be used to manipulate the NO system. Citrulline is a precursor of arginine, which is a common substrate for NO synthesis via any of the various NOS (Flynn et al. 2002). Fetal growth retardation induced by maternal undernutrition from day 28 to day 78 of gestation in sheep was associated with a decrease in arginine and citrulline in maternal plasma, fetal plasma, and allantoic fluid by 23–30% at day 78 of gestation (Kwon et al. 2004). Further, concentrations of biopterin (an indicator of de novo synthesis of tetrahydrobiopterin (BH4), which is an essential co-factor for NOS) in fetal plasma, and amniotic and allantoic fluids, were reduced by 32–36% in underfed ewes (G. Wu, unpublished results), perhaps indicating reduced availability of BH4 for NO production in the conceptus. These changes could impair placental and fetal NO synthesis, thereby resulting in reduced placental blood flow in underfed ewes (Bell & Ehrhardt, 2002; Kwon et al. 2004). Indeed, Xiao & Li (2005) recently reported that daily intravenous infusion of arginine for 7 days during late gestation (week 33), to women with unknown causes of fetal intrauterine growth restriction, resulted in a 6.4% increase in birth weight at term. Whether intravenous or oral administration of arginine could provide a therapeutic approach to consistently enhance fetal growth in compromised pregnancies, and whether its effects are via improved uterine and placental blood flows, are questions that, because of the simplicity of the approach, seem worthy of further investigation.

Conclusions

One of the remaining questions concerning compromised pregnancies is when in gestation are placental blood flows and angiogenesis affected and what mechanisms are responsible? In the overfed pregnant adolescent ewe, we recently found that uterine blood flow is reduced by 56% at day 90 of gestation, which is before any reduction in fetal or placental weights is observed (J. Wallace, M. Matsuzaki, J. S. Milne & R. P. Aitken, unpublished results, as cited in Wallace et al. 2005). This reduction in uterine blood flow corresponds with decreased expression of placental angiogenic factors, including VEGF and eNOS, by day 80 of gestation (Redmer et al. 2005), which is associated with altered placental vascular architecture late in pregnancy (Redmer et al. 2004a). Similarly, in heat-stressed ewes at day 55 of gestation, caruncular VEGF mRNA is unaltered but VEGF protein is reduced (Regnault et al. 2002a); for cotyledon, VEGF mRNA is elevated but protein is unaltered. These changes in angiogenic factor expression occurred before a reduction in fetal or placental weights (Regnault et al. 2002a) and were reflected by altered placental vascular architecture by day 90 (Regnault et al. 2002b). Thus, changes in placental blood flows and angiogenesis warrant further investigation in terms of their ontogeny, their regulation, and whether they occur in models of compromised pregnancy other than the overfed adolescent or heat-stressed adult.

The data we have summarized provide the basis for a convincing argument that restoration of placental blood flows and vascularity could provide an important therapeutic tool to manage compromised pregnancies for optimal fetal growth and development. However, it seems obvious that this strategy needs to be examined in much greater detail in various models of compromised pregnancy, and that it also will be important to establish whether the resulting ‘rescued’ fetuses or neonates are normal. It seems equally obvious that animal models of compromised pregnancy will be important in this effort.

Acknowledgments

We gratefully acknowledge the many individuals who have made valuable and important contributions to the progress of our work in this area, including our collaborators and colleagues (Dr Fuller Bazer, Dr Calvin Ferrell, Dr Stephen Ford, Dr Derek Killilea, Dr Ronald Magness and Dr Robert Moor), current and former graduate students (Mr Daniel Arnold, Dr Mary Lynn Johnson, Mr M. Carey Satterfield, Dr Abraham Scheaffer, Dr Marcy Ward and Dr Jing Zheng), numerous undergraduate students, and laboratory personnel (Mr Raymond Aitken, Dr Jerzy Bilski, Mr James Kirsch, Mr Kim Kraft, Mr John Milne and Mr Robert Weigl). We also gratefully acknowledge the North Dakota Agricultural Experiment Station, the Scottish Executive Environmental and Rural Affairs Department, the US Department of Agriculture, the US National Institutes of Health, and the US National Science Foundation, without whose funding we could not have accomplished nor continue this work.

References

  1. Ahmad S, Ahmed A. Antiangiogenic effect of soluble vascular endothelial growth factor receptor-1 in placental angiogenesis. Endothelium. 2005;12:89–95. doi: 10.1080/10623320590933888. [DOI] [PubMed] [Google Scholar]
  2. Ahmed A, Perkins J. Angiogenesis and intrauterine growth restriction. Baillieres Best Pract Res Clin Obstet Gynaecol. 2000;14:981–998. doi: 10.1053/beog.2000.0139. [DOI] [PubMed] [Google Scholar]
  3. Anderson CM, Lopez F, Zhang HY, Pavlish K, Benoit JN. Reduced uteroplacental perfusion alters uterine arcuate artery function in the pregnant Sprague-Dawley rat. Biol Reprod. 2005;72:762–766. doi: 10.1095/biolreprod.104.036715. [DOI] [PubMed] [Google Scholar]
  4. Arnold DR, Scheaffer AN, Redmer DA, Caton JS, Reynolds LP. Effect of nutrient restriction on placental vascularity and fetal growth in sheep. Biol Reprod. 2001;64(Suppl. 1):352. (Abstract 625) [Google Scholar]
  5. Barcroft J. Researches on Pre-Natal Life. Oxford: Blackwell; 1946. [Google Scholar]
  6. Barker DJ, Clark PM. Fetal undernutrition and disease in later life. Rev Reprod. 1997;2:105–112. doi: 10.1530/ror.0.0020105. [DOI] [PubMed] [Google Scholar]
  7. Bell AW, Ehrhardt RA. Regulation of placental nutrient transport and implications for fetal growth. Nutr Res Rev. 2002;15:211–230. doi: 10.1079/NRR200239. [DOI] [PubMed] [Google Scholar]
  8. Bell AW, Hay WW, Jr, Ehrhardt RA. Placental transport of nutrients and its implications for fetal growth. J Reprod Fertil Suppl. 1999;54:401–410. [PubMed] [Google Scholar]
  9. Bell AW, Kennaugh JM, Battaglia FC, Makowski EL, Meschia G. Metabolic and circulatory studies of fetal lamb at midgestation. Am J Physiol. 1986;250:E538–E544. doi: 10.1152/ajpendo.1986.250.5.E538. [DOI] [PubMed] [Google Scholar]
  10. Biensen NJ, Wilson ME, Ford SP. The impact of either a Meishan or Yorkshire uterus on Meishan or Yorkshire fetal and placental development to days 70, 90, and 110 of gestation. J Anim Sci. 1998;76:2169–2176. doi: 10.2527/1998.7682169x. [DOI] [PubMed] [Google Scholar]
  11. Bird IM, Zhang L, Magness RR. Possible mechanisms underlying pregnancy-induced changes in uterine artery endothelial function. Am J Physiol Regul Integr Comp Physiol. 2003;284:R245–R258. doi: 10.1152/ajpregu.00108.2002. [DOI] [PubMed] [Google Scholar]
  12. Borowicz PP, Vonnahme KA, Grazul-Bilska AT, Redmer DA, Johnson JL, Reynolds LP. The effect of maternal age (age at first pregnancy) on placental expression of the major angiogenic factors and their receptors. J Soc Gynecol Invest. 2005a;12(Suppl. 1):327A–328A. (Abstract 763) [Google Scholar]
  13. Borowicz PP, Ward MA, Caton JS, Soto-Navarro SA, Redmer DA, Taylor JB, Reynolds LP. Effects of supranutritional levels of selenium (Se) on vascular density and cell proliferation in the sheep placenta. J Anim Sci. 2005b;83(Suppl 2) (Abstract) (in press) [Google Scholar]
  14. Breier BH, Vickers MH, Ikenasio BA, Chan KY, Wong WP. Fetal programming of appetite and obesity. Molec Cell Endocrinol. 2001;20:73–79. doi: 10.1016/s0303-7207(01)00634-7. [DOI] [PubMed] [Google Scholar]
  15. Chandler KD, Leury BJ, Bird AR, Bell AW. Effects of undernutrition and exercise during late pregnancy on uterine, fetal and uteroplacental metabolism in the ewe. Br J Nutr. 1985;53:625–635. doi: 10.1079/bjn19850072. [DOI] [PubMed] [Google Scholar]
  16. Charnock-Jones DS, Kaufmann P, Mayhew TM. Aspects of human fetoplacental vasculogenesis and angiogenesis. I. Molecular regulation. Placenta. 2004;25:103–113. doi: 10.1016/j.placenta.2003.10.004. [DOI] [PubMed] [Google Scholar]
  17. Christenson RK, Prior RL. Uterine blood flow and nutrient uptake during late gestation in ewes with different number of fetuses. J Anim Sci. 1978;46:189–200. doi: 10.2527/jas1978.461189x. [DOI] [PubMed] [Google Scholar]
  18. Faber JJ, Thornburg KL. Placental Physiology. Structure and Function of Fetomaternal Exchange. New York: Raven Press; 1983. [Google Scholar]
  19. Ferrell CL. Placental regulation of fetal growth. In: Campion DR, Hausman GJ, Martin RJ, editors. Animal Growth Regulation. New York: Plenum; 1989. pp. 1–19. [Google Scholar]
  20. Flynn NE, Meininger CJ, Haynes TE, Wu G. The metabolic basis of arginine nutrition and pharmacotherapy. Biomed Pharmacother. 2002;56:427–438. doi: 10.1016/s0753-3322(02)00273-1. [DOI] [PubMed] [Google Scholar]
  21. Gadelha Da Costa A, Mauad Filho F, Spara P, Barreto Gadelha E, Vieira Santana Netto P. Fetal hemodynamics evaluated by Doppler velocimetry in the second half of pregnancy. Ultrasound Med Biol. 2005;31:1023–1030. doi: 10.1016/j.ultrasmedbio.2005.04.009. [DOI] [PubMed] [Google Scholar]
  22. Godfrey KM. The role of the placenta in fetal programming – a review. Placenta. 2002;23(Suppl A):S20–S27. doi: 10.1053/plac.2002.0773. [DOI] [PubMed] [Google Scholar]
  23. Grazul-Bilska AT, Pant D, Luther JS, Borowicz PP, Navanukraw C, Caton JS, Ward MA, Redmer DA, Reynolds LP. Pregnancy rates and gravid uterine parameters in single, twin and triplet pregnancies in naturally bred ewes and ewes after transfer of in vitro produced embryos. Anim Reprod Sci. 2006 doi: 10.1016/j.anireprosci.2005.06.013. DOI 10.1016/j.anireprosci.2005.06.013. [DOI] [PubMed] [Google Scholar]
  24. Huppertz B, Peeters LL. Vascular biology in implantation and placentation. Angiogenesis. 2005;8:157–167. doi: 10.1007/s10456-005-9007-8. [DOI] [PubMed] [Google Scholar]
  25. Itoh H, Bird IM, Nakao K, Magness RR. Pregnancy increases soluble and particulate guanylate cyclases and decreases the clearance receptor of natriuretic peptides in ovine uterine, but not systemic, arteries. Endocrinology. 1998;139:3329–3341. doi: 10.1210/endo.139.7.6093. [DOI] [PubMed] [Google Scholar]
  26. Joyce JM, Phernetton TM, Shaw CE, Modrick ML, Magness RR. Endothelial vasodilator production by uterine and systemic arteries. IX. eNOS gradients in cycling and pregnant ewes. Am J Physiol Heart Circ Physiol. 2002;282:H342–H348. doi: 10.1152/ajpheart.00438.2001. [DOI] [PubMed] [Google Scholar]
  27. Kaufmann P, Mayhew TM, Charnock-Jones DS. Aspects of human fetoplacental vasculogenesis and angiogenesis. II. Changes during normal pregnancy. Placenta. 2004;25:114–126. doi: 10.1016/j.placenta.2003.10.009. [DOI] [PubMed] [Google Scholar]
  28. Kelly RW. Nutrition and placental development. Proc Nutr Soc Australia. 1992;17:203–211. [Google Scholar]
  29. Konje JC, Howarth ES, Kaufmann P, Taylor DJ. Longitudinal quantification of uterine artery blood volume flow changes during gestation in pregnancies complicated by intrauterine growth restriction. Br J Obstet Gynecol. 2003;110:301–305. [PubMed] [Google Scholar]
  30. Krebs C, Longo LD, Leiser R. Term ovine placental vasculature: Comparison of sea level and high altitude conditions by corrosion cast and histomorphometry. Placenta. 1997;18:43–51. doi: 10.1016/s0143-4004(97)90070-9. [DOI] [PubMed] [Google Scholar]
  31. Kwon H, Ford SP, Bazer FW, Spencer TE, Nathanielsz PW, Nijland MJ, Hess BW, Wu G. Maternal nutrient restriction reduces concentrations of amino acids and polyamines in ovine maternal and fetal plasma and fetal fluids. Biol Reprod. 2004;71:901–908. doi: 10.1095/biolreprod.104.029645. [DOI] [PubMed] [Google Scholar]
  32. Leury BJ, Bird AR, Chandler KD, Bell AW. Glucose partitioning in the pregnant ewe: effects of undernutrition and exercise. Br J Nutr. 1990;64:449–462. doi: 10.1079/bjn19900045. [DOI] [PubMed] [Google Scholar]
  33. Luther JS, Redmer DA, Reynolds LP, Wallace JM. Nutritional paradigms of ovine fetal growth restriction: implications for human pregnancy. Human Fertil. 2005;8:179–187. doi: 10.1080/14647270500320121. [DOI] [PubMed] [Google Scholar]
  34. Magness RR. Maternal cardiovascular and other physiological responses to the endocrinology of pregnancy. In: Bazer FW, editor. The Endocrinology of Pregnancy. Totowa, NJ: Humana Press; 1998. pp. 507–539. [Google Scholar]
  35. Magness RR, Sullivan JA, Li Y, Phernetton TM, Bird IM. Endothelial vasodilator production by uterine and systemic arteries. VI. Ovarian and pregnancy effects on eNOS and NO(x) Am J Physiol Heart Circ Physiol. 2001;280:H1692–H1698. doi: 10.1152/ajpheart.2001.280.4.H1692. [DOI] [PubMed] [Google Scholar]
  36. Makowski EL, Meschia G, Droegmueller W, Battaglia FC. Distribution of uterine blood flow in the pregnant sheep. Am J Obstet Gynecol. 1968a;101:409–412. doi: 10.1016/0002-9378(68)90074-4. [DOI] [PubMed] [Google Scholar]
  37. Makowski EL, Meschia G, Droegmueller W, Battaglia FC. Measurement of umbilical arterial blood flow to the sheep placenta and fetus in utero. Circ Res. 1968b;23:623–631. doi: 10.1161/01.res.23.5.623. [DOI] [PubMed] [Google Scholar]
  38. Maul H, Longo M, Saade GR, Garfield RE. Nitric oxide and its role during pregnancy: from ovulation to delivery. Curr Pharm Des. 2003;9:359–380. doi: 10.2174/1381612033391784. [DOI] [PubMed] [Google Scholar]
  39. Mayhew TM, Charnock-Jones DS, Kaufmann P. Aspects of human fetoplacental vasculogenesis and angiogenesis. III. Changes in complicated pregnancies. Placenta. 2004;25:127–139. doi: 10.1016/j.placenta.2003.10.010. [DOI] [PubMed] [Google Scholar]
  40. Meschia G. Circulation to female reproductive organs. In: Shepherd JT, Abboud FM, editors. Handbook of Physiology. III. Bethesda, MD: American Physiological Society; 1983. pp. 241–269. Sect. 2, part 1. [Google Scholar]
  41. Metcalfe J, Stock MK, Barron DH. Maternal physiology during gestation. In: Knobil E, Neill J, Ewing JJ, Greenwald GS, Markert CL, Pfaff DW, editors. The Physiology of Reproduction. New York: Raven Press; 1988. pp. 2145–2176. [Google Scholar]
  42. Michel T. Treatment of myocardial ischemia. In: Brunton LL, Lazo JS, Parker KL, editors. Goodman and Gilman's the Pharmacological Basis of Therapeutics. 11. New York: McGraw-Hill; 2006. pp. 823–844. [Google Scholar]
  43. Molina RD, Meschia G, Battaglia FC, Hay WW., Jr Gestational maturation of placental glucose transfer capacity in sheep. Am J Physiol. 1991;261:R697–R704. doi: 10.1152/ajpregu.1991.261.3.R697. [DOI] [PubMed] [Google Scholar]
  44. Moore LG, Shriver M, Bemis L, Hickler B, Wilson M, Brutsaert T, Parra E, Vargas E. Maternal adaptation to high-altitude pregnancy: An experiment of nature – a review. Placenta. 2004;25(Suppl. A):S60–S71. doi: 10.1016/j.placenta.2004.01.008. (Trophoblast Research 18) [DOI] [PubMed] [Google Scholar]
  45. Mossman HW. Vertebrate Fetal Membranes. New Brunswick, NJ: Rutgers University Press; 1987. [Google Scholar]
  46. Newnham JP, Kelly RW, Patterson L, James I. The influence of maternal undernutrition in ovine twin pregnancy on fetal growth and Doppler flow-velocimetry waveforms. J Dev Physiol. 1991;16:277–282. [PubMed] [Google Scholar]
  47. NLM. Adolescent Pregnancy. 2002a. National Library of Medicine, MEDLINEplus. http://www.nlm.nih.gov/medlineplus/ency/article/001516.htm#prognosis.
  48. NLM. Intrauterine Growth Restriction. 2002b. National Library of Medicine, MEDLINEplus. http://www.nlm.nih.gov/medlineplus/ency/article/001500.htm.
  49. North RA, Ferrier C, Long D, Townend K, Kincaid-Smith P. Uterine artery Doppler flow velocity waveforms in the second trimester for the prediction of preeclampsia and fetal growth retardation. Obstet Gynecol. 1994;83:378–386. [PubMed] [Google Scholar]
  50. NVSR. National Vital Statistics Reports. 2004. no. 9 (DHHS Publication no. (PHS) 2005-1120 PRS 05-0046 (11/2004)) http://www.cdc.gov/nchs/data/nvsr/nvsr53/nvsr53_09.pdf.
  51. Parraguez VH, Atlagich M, Díaz R, Cepeda R, González C, De los Reyes M, Bruzzone ME, Behn C, Raggi LA. Ovine placenta at high altitudes: comparison of animals with different times of adaptation to hypoxic environment. Anim Reprod Sci. 2006 doi: 10.1016/j.anireprosci.2005.11.003. DOI 10.1016/j.anireprosci.2005.11.003. [DOI] [PubMed] [Google Scholar]
  52. Poston L. The control of blood flow to the placenta. Exp Physiol. 1997;82:377–387. doi: 10.1113/expphysiol.1997.sp004033. [DOI] [PubMed] [Google Scholar]
  53. Ramsey EM. The Placenta, Human and Animal. New York: Praeger; 1982. [Google Scholar]
  54. Redmer DA, Aitken RP, Milne JS, Borowicz PP, Borowicz MA, Kraft KD, Reynolds LP, Luther JS, Wallace JM. Influence of maternal nutrition on placental vascularity during late pregnancy in adolescent ewes. Biol Reprod. 2004a;70(Suppl 1):150. [Google Scholar]
  55. Redmer DA, Aitken RP, Milne JS, Reynolds LP, Wallace JM. Influence of maternal nutrition on messenger rna expression of placental angiogenic factors and their receptors at mid-gestation in adolescent sheep. Biol Reprod. 2005;72:1004–1009. doi: 10.1095/biolreprod.104.037234. [DOI] [PubMed] [Google Scholar]
  56. Redmer DA, Wallace JM, Reynolds LP. Effects of nutrient intake during pregnancy on fetal and placental growth and vascular development. Domestic Anim Endocrinol. 2004b;27:199–217. doi: 10.1016/j.domaniend.2004.06.006. [DOI] [PubMed] [Google Scholar]
  57. Regnault TR, de Vrijer B, Galan HL, Davidsen ML, Trembler KA, Battaglia FC, Wilkening RB, Anthony RV. The relationship between transplacental O2 diffusion and placental expression of PlGF, VEGF and their receptors in a placental insufficiency model of fetal growth restriction. J Physiol. 2003;550:641–656. doi: 10.1113/jphysiol.2003.039511. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Regnault TR, Galan HL, Parker TA, Anthony RV. Placental development in normal and compromised pregnancies – a review. Placenta. 2002a;23(Suppl A):S119–S129. doi: 10.1053/plac.2002.0792. [DOI] [PubMed] [Google Scholar]
  59. Regnault TR, Orbus RJ, Vrijer B, Davidsen ML, Galan HL, Wilkening RB, Anthony RV. Placental expression of VEGF, PlGF and their receptors in a model of placental insufficiency-intrauterine growth restriction (PI-IUGR) Placenta. 2002b;23:132–144. doi: 10.1053/plac.2001.0757. [DOI] [PubMed] [Google Scholar]
  60. Reynolds LP, Borowicz PP, Vonnahme KA, Johnson ML, Grazul-Bilska AT, Redmer DA, Caton JS. Placental angiogenesis in sheep models of compromised pregnancy. J Physiol. 2005a;565:43–58. doi: 10.1113/jphysiol.2004.081745. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Reynolds LP, Borowicz PP, Vonnahme KA, Johnson ML, Grazul-Bilska AT, Wallace JM, Caton JS, Redmer DA. Animal models of placental angiogenesis. Placenta. 2005b;26:689–708. doi: 10.1016/j.placenta.2004.11.010. [DOI] [PubMed] [Google Scholar]
  62. Reynolds LP, Ferrell CL. Transplacental clearance and blood flows of bovine gravid uterus at several stages of gestation. Am J Physiol. 1987;253:R735–R739. doi: 10.1152/ajpregu.1987.253.5.R735. [DOI] [PubMed] [Google Scholar]
  63. Reynolds LP, Ferrell CL, Nienaber JA, Ford SP. Effects of chronic environmental heat-stress on blood flow and nutrient uptake of the gravid bovine uterus and foetus. J Agric Sci. 1985;104:289–297. [Google Scholar]
  64. Reynolds LP, Ferrell CL, Robertson DA, Ford SP. Metabolism of the gravid uterus, foetus and uteroplacenta at several stages of gestation in cows. J Agric Sci (Camb) 1986;106:437–444. [Google Scholar]
  65. Reynolds LP, Redmer DA. Utero-placental vascular development and placental function. J Anim Sci. 1995;73:1839–1851. doi: 10.2527/1995.7361839x. [DOI] [PubMed] [Google Scholar]
  66. Reynolds LP, Redmer DA. Minireview: Angiogenesis in the placenta. Biol Reprod. 2001;64:1033–1040. doi: 10.1095/biolreprod64.4.1033. [DOI] [PubMed] [Google Scholar]
  67. Rosenfeld CR, Morriss FH, Makowski EL, Meschia G, Battaglia FC. Circulatory changes in the reproductive tissues of ewes during pregnancy. Gynecol Invest. 1974;5:252–268. doi: 10.1159/000301658. [DOI] [PubMed] [Google Scholar]
  68. Rudolph AM, Heymann MA. Circulatory changes during growth in the fetal lamb. Circ Res. 1970;26:289–299. doi: 10.1161/01.res.26.3.289. [DOI] [PubMed] [Google Scholar]
  69. Rupnow HL, Phernetton TM, Shaw CE, Modrick ML, Bird IM, Magness RR. Endothelial vasodilator production by uterine and systemic arteries. VII. Estrogen and progesterone effects on eNOS. Am J Physiol Heart Circ Physiol. 2001;280:H1699–H1705. doi: 10.1152/ajpheart.2001.280.4.H1699. [DOI] [PubMed] [Google Scholar]
  70. Scheaffer AN, Caton JS, Arnold DR, Reynolds LP. Impact of feeding level and type of fetus in different ewe types on fetal weight, maternal body weight, and organ mass in mature ewes. J Anim Sci. 2004;82:1826–1838. doi: 10.2527/2004.8261826x. [DOI] [PubMed] [Google Scholar]
  71. Sladek SM, Magness RR, Conrad KP. Nitric oxide and pregnancy. Am J Physiol. 1997;272:R441–R463. doi: 10.1152/ajpregu.1997.272.2.R441. [DOI] [PubMed] [Google Scholar]
  72. Thureen PJ, Trembler KA, Meschia G, Makowski EL, Wilkening RB. Placental glucose transport in heat-induced fetal growth retardation. Am J Physiol. 1992;263:R578–R585. doi: 10.1152/ajpregu.1992.263.3.R578. [DOI] [PubMed] [Google Scholar]
  73. Trudinger BJ, Giles WB, Cook CM. Uteroplacental blood flow velocity-time waveforms in normal and complicated pregnancy. Br J Obstet Gynecol. 1985;92:39–45. doi: 10.1111/j.1471-0528.1985.tb01046.x. [DOI] [PubMed] [Google Scholar]
  74. Vagnoni KE, Shaw CE, Phernetton TM, Meglin BM, Bird IM, Magness RR. Endothelial vasodilator production by uterine and systemic arteries. III. Ovarian and estrogen effects on NO synthase. Am J Physiol. 1998;275:H1845–H1856. doi: 10.1152/ajpheart.1998.275.5.H1845. [DOI] [PubMed] [Google Scholar]
  75. Vonnahme KA, Ford SP. Differential expression of the vascular endothelial growth factor-receptor system in the gravid uterus of yorkshire and Meishan pigs. Biol Reprod. 2004;71:163–169. doi: 10.1095/biolreprod.103.026344. [DOI] [PubMed] [Google Scholar]
  76. Vonnahme KA, Ford SP, Nijland MJ, Reynolds LP. Alteration in cotyledonary (COT) vascular responsiveness to angiotensin II (ANG II) in beef cows undernourished during early gestation. Bio Reprod. 2004a;70(Suppl 1):110. [Google Scholar]
  77. Vonnahme KA, Hess BW, Hansen TR, McCormick RJ, Rule DC, Moss GE, Murdoch WJ, Nijland M, Skinner DC, Nathanielsz PW, Ford SP. Maternal undernutrition from early- to mid-gestation leads to growth retardation cardiac ventricular hypertrophy, and increased liver weight in the fetal sheep. Biol Reprod. 2003;69:133–140. doi: 10.1095/biolreprod.102.012120. [DOI] [PubMed] [Google Scholar]
  78. Vonnahme KA, Reynolds LP, Nijland MJ, Ford SP. Impacts of undernutrition during early to mid gestation on basal vascular tone of the cotyledonary and caruncular arterial beds in the bovine placentome. J Soc Gynecol Invest. 2004b;11(Suppl):222A. [Google Scholar]
  79. Vonnahme KA, Wilson ME, Li Y, Rupnow HL, Phernetton TM, Ford SP, Magness RR. Circulating levels of nitric oxide and vascular endothelial growth factor throughout ovine pregnancy. J Physiol. 2005;565:101–109. doi: 10.1113/jphysiol.2004.082321. [DOI] [PMC free article] [PubMed] [Google Scholar]
  80. Wallace JM, Bourke DA, Aitken RP, Leitch N, Hay WW., Jr Blood flows and nutrient uptakes in growth-restricted pregnancies induced by overnourishing adolescent sheep. Am J Physiol. 2002;282:R1027–R1036. doi: 10.1152/ajpregu.00465.2001. [DOI] [PubMed] [Google Scholar]
  81. Wallace JM, Regnault TR, Limesand SW, Hay WW, Jr, Anthony RV. Investigating the causes of low birth weight in contrasting ovine paradigms. J Physiol. 2005;565:19–26. doi: 10.1113/jphysiol.2004.082032. [DOI] [PMC free article] [PubMed] [Google Scholar]
  82. Wareing M, Baker PN. Vasoconstriction of small arteries isolated from the human placental chorionic plate in normal and compromised pregnancy. Hypertens Pregnancy. 2004;23:237–246. doi: 10.1081/PRG-200030297. [DOI] [PubMed] [Google Scholar]
  83. Wareing M, Myers JE, O'Hara M, Baker PN. Sildenafil citrate (Viagra) enhances vasodilatation in fetal growth restriction. J Clin Endocrinol Metab. 2005;90:2550–2555. doi: 10.1210/jc.2004-1831. [DOI] [PubMed] [Google Scholar]
  84. Wilson ME, Biensen NJ, Youngs CR, Ford SP. Development of Meishan and Yorkshire littermate conceptuses in either a Meishan or Yorkshire uterine environment to day 90 of gestation and to term. Biol Reprod. 1998;58:905–910. doi: 10.1095/biolreprod58.4.905. [DOI] [PubMed] [Google Scholar]
  85. Wu G, Bazer FW, Cudd TA, Meininger CJ, Spencer TE. Maternal nutrition and fetal development. J Nutr. 2004;134:2169–2172. doi: 10.1093/jn/134.9.2169. [DOI] [PubMed] [Google Scholar]
  86. Xiao XM, Li LP. 1-arginine treatment for asymmetric fetal growth restriction. Int J Gynecol Obstet. 2005;88:15–18. doi: 10.1016/j.ijgo.2004.09.017. [DOI] [PubMed] [Google Scholar]
  87. Zamudio S, Palmer SK, Droma T, Stamm E, Coffin C, Moore LG. Effect of altitude on uterine artery blood flow during normal pregnancy. J Appl Physiol. 1995;79:7–14. doi: 10.1152/jappl.1995.79.1.7. [DOI] [PubMed] [Google Scholar]
  88. Zheng J, Li Y, Weiss AR, Bird IM, Magness RR. Expression of endothelial and inducible nitric oxide synthases and nitric oxide production in ovine placental and uterine tissues during late pregnancy. Placenta. 2000;21:516–524. doi: 10.1053/plac.1999.0504. [DOI] [PubMed] [Google Scholar]
  89. Zoma WD, Baker RS, Clark KE. Effects of combined use of sildenafil citrate (Viagra) and 17beta-estradiol on ovine coronary and uterine hemodynamics. Am J Obstet Gynecol. 2004;190:1291–1297. doi: 10.1016/j.ajog.2003.12.021. [DOI] [PubMed] [Google Scholar]

Articles from The Journal of Physiology are provided here courtesy of The Physiological Society

RESOURCES