Placental Vascular Development Research Articles

Choline affects placental vascular function and development in a dose response manner

This study explored the role of choline in placental vascular function. In a 12‐week controlled feeding study among third trimester pregnant women, the higher choline intake group (930 vs. 480 mg/d) had lower (P=0.05) placental and circulating levels of soluble fms‐like tyrosine kinase‐1 (sFLT1), an anti‐angiogenic factor that predicts preeclampsia risk. The effect of choline on placental cell function was further investigated using immortalized HTR‐8/SVneo trophoblasts cultured in different choline concentrations (28, 13 and 8 μM) for 96 hours. The decrease in choline concentrations led to a graded increase (P<0.01) in the gene expression and secretion of sFLT1, expression of the proinflammatory markers [e.g. interleukin 1 beta (IL1B)], apoptosis and oxidative stress. Cellular phosphatidylcholine dramatically decreased (50%, P<0.01) in the lower choline group, whereas the protein kinase C (PKC) isoforms δ and ε, activated by breakdown products of phosphatidylcholine, increased (P<0.01). The addition of a PKC inhibitor partially rescued the increased expression of sFLT1 and apoptosis. In conclusion, choline influences placental vascular function partially via PKC.Grant Funding Source: USDA NIFA AFRI003397

Identification of soluble CD146 as a regulator of trophoblast migration: potential role in placental vascular development

Both vasculogenesis and angiogenesis occur during normal placental vascular development. Additionally, the placenta undergoes a process of vascular mimicry (pseudo-vasculogenesis) where the placental extravillous trophoblast (EVT) that invade the spiral arteries convert from an epithelial to an endothelial phenotype during normal pregnancy. As soluble CD146 (sCD146) constitutes a new physiological factor with angiogenic properties, we hypothesized that it could be involved in the regulation of placental vascular development by acting on EVT. Using placental villous explants, we demonstrated that sCD146 inhibits EVT outgrowth. Consistently, we showed that sCD146 inhibits the ability of EVT cells (HTR8/SVneo) to migrate, invade and form tubes in Matrigel, without affecting their proliferation or apoptosis. The involvement of sCD146 in human pregnancy was investigated by evaluation of sCD146 levels in 50 pregnant women. We observed physiological down-regulation of sCD146 throughout pregnancy. These results prompted us to investigate the effect of prolonged sCD146 administration in a rat model of pregnancy. Repeated systemic sCD146 injections after coupling caused a significant decrease of pregnancy rate and number of embryos. Histological studies performed on placenta evidenced a reduced migration of glycogen cells (analogous to EVT in rat) in sCD146-treated rats. We propose that in human, sCD146 could represent both an attractive biomarker of placental vascular development and a therapeutic target in pregnancy complications associated with pathological angiogenesis.

Expression of Sex Steroid Receptors in Ovine Placental Tissues During Early Pregnancy: Effects of Assisted Reproductive Technologies (ART).

Placental development can be compromised by genetic, epigenetic, environmental, or other factors, leading to poor fetal growth as well as poor pregnancy and postnatal outcomes. Pregnancies established with ART generate especially poor pregnancies (for example, only approximately 40 to 50% of IVF and less than 10% of cloned embryos survive to birth) that are associated with altered vascularization of the placenta. We have shown recently that these placental vascular defects in pregnancies from ART occur within the first few weeks of pregnancy in sheep, at approximately the same time at which substantial embryonic loss begins. Sex steroids and their receptors are important regulators of angiogenesis and growth in reproductive tissues, including the placenta. However, little is known about the expression of sex steroid receptors in placental tissues during early pregnancy or how ART affects their expression. We hypothesized that ART would affect the expression of estrogen receptor alpha and beta, nuclear progesterone receptor, and membrane progesterone receptors alpha, beta, and gamma in utero-placental tissues during early pregnancy in sheep. Pregnancies (n = 7 per group) were achieved through natural breeding (NAT, control), or transfer of embryos generated through natural breeding (NAT-ET), in vitro fertilization (IVF), or in vitro activation (IVA; parthenogenetic clones). On day 22 of pregnancy, samples of caruncle (CAR; maternal utero-placenta) and fetal membranes (FM; fetal placenta [chorioallantois]) were snap-frozen separately for RNA extraction followed by quantitative real-time RT-PCR. In CAR, mRNA expression of estrogen receptor alpha and nuclear progesterone receptor was decreased (P < 0.001) by 64 to 86% in NAT-ET, IVF, and IVA groups compared with NAT. In contrast, in FM mRNA expression of estrogen receptor alpha tended (P = 0.1) to be 2.5- to 6.4-fold greater in the IVA group compared with NAT and NAT-ET, which were similar; expression of estrogen receptor alpha was intermediate in the IVF group. Expression of mRNA for nuclear progesterone receptor in FM, and for estrogen receptor beta and membrane progesterone receptors alpha, beta, and gamma in CAR and FM, did not differ among the pregnancy-type groups. Because sex steroids are critical regulators of utero-placental vascularization, growth, and function, these data suggest that altered expression of placental sex steroid receptors may be an early event leading to poor placental vascularization and growth after ART. These data also provide a basis for understanding the mechanisms by which sex steroids regulate placental growth and vascular development in normal and compromised pregnancies. Supported by USDA 2007-01215 to LPR and ATGB, and NIH HL64141 to LPR and DAR.

PP131. Regulation of heme oxygenase/carbon monoxide (ho/co) and l-arginine/nitric oxide (no) pathways by human chorionic gonadotropin (hcg) in human fetal endothelium

HO/CO and l-arginine/NO pathways are critical regulators of vascular function in early human pregnancy. HO is the rate-limiting enzyme in heme catabolism leading to the formation of biliverdin, which is subsequently reduced to bilirubin by biliverdin reductase, carbon monoxide, and free iron. HO-1, the inducible isoform of the enzyme, is essential to promote placental function and fetal development (1). HO-1 is also required to maintain nitric oxide synthesis (2). Human chorionic gonadotropin (hCG) is the first blastocyst-derived hormonal signal playing a significant role in implantation and placentation (3). We hypothesized that hCG upregulates HO-1 and thus positively regulates early vascular events in human pregnancy. In this study we used human umbilical vein endothelial cells (HUVECs) to demonstrate that hCG up-regulates mRNA and protein abundance of HO-1. The effect of hCG on l-arginine transport and the expression of hCAT1, the main cationic amino acid transporter involved in endothelial nitric oxide synthesis were evaluated. HUVEC were isolated from normal pregnancies (approval from the Institutional Review Board) by collagenase digestion and grown (37°C, 5% CO2) in medium 199 supplemented with 20% newborn and fetal calf sera. Cells were treated with hCG (0.5-100IU/mL, 0-24hours and CoCl2 (150μM, 6hours) as positive control. Total proteins were separated by SDS-PAGE electrophoresis, transferred to nitrocellulose membranes and incubated with monoclonal anti human HO-1 or anti β-actin and respective secondary antibody conjugated with horseradish peroxidase. Protein bands were detected by enhanced chemiluminiscence. Total RNA was isolated and cDNA was obtained by reverse transcription. PCR assays were performed in a reaction mix containing 0.5μM primers, dNTPs, Taq DNA polymerase, 2 mM MgCl2. Relative abundance of HO-1, hCAT-1 and 28S were determined. l-[(3)H]Arginine transport (100μM, 2 μCi ml(-1), 37°C, 1min) were determined in HUVECs exposed (30min) to hCG (0.5-100IU/mL) and CORM-2 (CO donor). The highest level of HO-1 protein were obtained at 5IU/mL of hCG and declined at higher concentrations. hCG increased HO-1 protein abundance and maximal response was observed at 6 hours (4-fold), decreasing at 24hours exposure. These effects of hCG on HO-1 protein abundance are well correlated with changes in HO-1 mRNA regarding time of exposure and concentration of hCG. L-arginine transport and hCAT-1 mRNA were also increased (2.8-fold and 4.5-fold, respectively) by hCG. Upregulation of HO-1 as well as the increase in l-arginine transport and hCAT-1 mRNA in HUVECs are novel effects of hCG, which occur at physiological plasma concentrations of the hormone, as those found in the first weeks of pregnancy. These changes could be relevant for the maintenance of the NO synthesis in fetal and maternal vasculature, ensuring the predominance of the vasodilator tone. These effects could be also critical for vascular remodelling of uterine circulation and placental vascular development in early stages of pregnancy, the lack of which could result in abnormal placentation as described in preeclampsia and fetal growth restriction.

A deficiency in haem oxygenase‐1 induces foetal growth restriction by placental vasculature defects

Haem oxygenase-1 (HO-1), the rate-limiting enzyme in haem degradation, plays a role in angiogenesis and vasculogenesis and is highly expressed in the placenta. Deficiencies in HO-1 are associated with several pregnancy disorders, such as recurrent miscarriages and pre-eclampsia. The unique combination of tissue protective, smooth muscle relaxing and angiogenesis regulatory properties makes HO-1 a key player in the maintenance of a healthy pregnancy through a direct effect on placental structural and vascular development, thus affecting foetal development. Therefore, we conclude that HO-1 plays an important role in placental vasculature development and a deficiency in HO-1 may contribute to pregnancy complications, such as pre-eclampsia, spontaneous abortions and premature births.

Estrogen synthesis genes CYP19A1, HSD3B1, and HSD3B2 in hypertensive disorders of pregnancy

Hypertension in pregnancy is a multifactorial disorder caused by a complex combination of environmental factors and several predisposing genes. Since estrogen modulates placental vascular development, estrogen synthases are considered plausible candidate genes. The aim of this haplotype-based case-control study was to estimate whether polymorphisms of the maternal estrogen synthesis genes (CYP19A1, HSD3B1 and HSD3B2) are associated with preeclampsia (PE) and gestational hypertension (GH). To examine the genetic markers in 69 PE and 62 GH patients and in 155 age-matched, primiparous, healthy control subjects, genotyping of 5 SNPs for the CYP19A1 gene (rs1870049, rs936306, rs700518, rs700519, and rs4646), 3 SNPs for the HSD3B1 gene (rs3765945, rs6203, and rs1047303), and 2 SNPs for the HSD3B2 gene (rs2854964 and rs1819698) was performed. For rs700158 of CYP19A1, the frequencies of the AG+GG genotype and the G allele were significantly higher in PE as compared to controls (P = 0.037, P = 0.033, respectively). Logistic regression analyses indicated that the AG+GG genotype of rs700158 was a PE risk factor (odds ratio = 2.15, P = 0.026). In addition, the frequency of the G-G haplotype established by rs700518-rs4646 was also significantly higher for PE (P = 0.017). These data suggest that the estrogen synthesis gene, CYP19A1 is associated with PE in the Japanese population.

Angiogenic Factors in Preeclampsia and Related Disorders

During fetal development, the human placenta undergoes high levels of both angiogenesis and vasculogenesis. Additionally, the developing placenta undergoes a process of vascular mimicry (referred to as pseudovasculogenesis) as cytotrophoblasts convert from an epithelial to an endothelial phenotype. The initiation, maturation, and maintenance of the placental vasculature are of critical importance. Failure to do so can lead to adverse obstetric outcomes such as preeclampsia and/or intrauterine growth restriction (IUGR). Furthermore, the foundation of many aspects of adult health is laid in utero. In this context, normal placental function is not only critical for normal fetal development but can also permanently influence long-term health and disease. Understanding the mechanisms that regulate placental vasculogenesis and angiogenesis is therefore of critical importance. This chapter will focus on placental vascular development with a particular emphasis on the role of angiogenic factors in the pathogenesis of the maternal syndrome of preeclampsia and related disorders.

Mast Cells and Histamine: Do They Influence Placental Vascular Network and Development in Preeclampsia?

The physiological course of pregnancy is closely related to adequate development of the placenta. Shallow invasion of trophoblast as well as decreased development of the placental vascular network are both common features of preeclampsia. To better understand the proangiogenic features of mast cells, in this study we aim to identify the potential relationship between the distribution of mast cells within the placenta and vascular network development. Material and Methods. Placentas from preeclampsia-complicated pregnancies (n = 11) and from physiological pregnancies (n = 11) were acquired after cesarean section. The concentration of histamine was measured, and immunohistochemical staining for mast cell tryptase was performed. Morphometric analysis was then performed. Results. We noticed significant differences between the examined groups. Notably, in the preeclampsia group compared to the control group, we observed a higher mean histamine concentration, higher mast cell density (MCD), lower mean mast cell (MMCA) and lower vascular/extravascular (V/EVT) index. In physiological pregnancies, a positive correlation was observed between the histamine concentration and V/VEVT index as well as MCD and the V/VEVT index. In contrast, a negative correlation was observed between MMCA and the V/EVT index in physiological pregnancies. Conclusions. Based on the data from our study, we suggest that a differential distribution of mast cells and corresponding changes in the concentration of histamine are involved in the defective placental vascularization seen in preeclamptic placentas.

Assessment of placental growth factor and soluble vascular endothelial growth factor receptor 1 in the prediction of pre-eclampsia

Background Pre-eclampsia is a pregnancy-associated disease occurring in 5–8% of pregnancies and is a major cause of maternal and fetal morbidity and mortality. A potentially important process in the pathogenesis of pre-eclampsia is an imbalance between placenta-derived proangiogenic and antiangiogenic proteins. The proangiogenic proteins vascular endothelial growth factor (VEGF) and placental growth factor (PLGF) are involved in the regulation of placental vascular development and maternal endothelial function during pregnancy. Aim of the study The aim of this study is to assess the PLGF and soluble vascular endothelial growth factor receptor 1 (sVEGFR-1) in the prediction of pre-eclampsia. Materials and methods This study included 88 pregnant women: 68 pregnant women with pre-eclampsia divided into two subgroups (mild and severe pre-eclampsia) and 20 healthy pregnant women matched for age and sex, who served as the control group. Laboratory investigations such as determination of complete blood count, blood urea, serum creatinine, aspartate aminotransferase, alanine transaminase, serum albumin, quantitative determination of total protein in urine, estimation of prothrombin time and concentration, serum PLGF concentration, and serum sVEGFR-1 concentrations were carried out by ELISA. BMI was estimated in this study. Results The results showed that serum PLGF was highly significant decreased in women with pre-eclampsia when compared with the control group. There was a highly statistically significant difference between mild and severe cases, where the PLGF decreased with increased severity of pre-eclampsia (P Conclusion Finally, it is concluded that high concentrations of sVEGFR-1 combined with low concentrations of PLGF may be used to predict the development of pre-eclampsia.

Role of nitric oxide in placental vascular development and function

Nitric oxide (NO) is one of the most pleiotropic signaling molecules at systemic and cellular levels, participating in vascular tone regulation, cellular respiration, proliferation, apoptosis and gene expression. Indeed NO actively participates in trophoblast invasion, placental development and represents the main vasodilator in this tissue. Despite the large number of studies addressing the role of NO in the placenta, its participation in placental vascular development and the effect of altered levels of NO on placental function remains to be clarified. This review draws a time-line of the participation of NO throughout placental vascular development, from the differentiation of vascular precursors to the consolidation of vascular function are considered. The influence of NO on cell types involved in the origin of the placental vasculature and the expression and function of the nitric oxide synthases (NOS) throughout pregnancy are described. The developmental processes involved in the placental vascular bed are considered, such as the participation of NO in placental vasculogenesis and angiogenesis through VEGF and Angiopoietin signaling molecules. The role of NO in vascular function once the placental vascular tree has developed, in normal pregnancy as well as in pregnancy-related diseases, is then discussed.

Metabolic Profiling Uncovers a Phenotypic Signature of Small for Gestational Age in Early Pregnancy

Being born small for gestational age (SGA) confers increased risks of perinatal morbidity and mortality and increases the risk of cardiovascular complications and diabetes in later life. Accumulating evidence suggests that the etiology of SGA is usually associated with poor placental vascular development in early pregnancy. We examined metabolomic profiles using ultra performance liquid chromatography-mass spectrometry (UPLC-MS) in three independent studies: (a) venous cord plasma from normal and SGA babies, (b) plasma from a rat model of placental insufficiency and controls, and (c) early pregnancy peripheral plasma samples from women who subsequently delivered a SGA baby and controls. Multivariate analysis by cross-validated Partial Least Squares Discriminant Analysis (PLS-DA) of all 3 studies showed a comprehensive and similar disruption of plasma metabolism. A multivariate predictive model combining 19 metabolites produced by a Genetic Algorithm-based search program gave an Odds Ratio for developing SGA of 44, with an area under the Receiver Operator Characteristic curve of 0.9. Sphingolipids, phospholipids, carnitines, and fatty acids were among this panel of metabolites. The finding of a consistent discriminatory metabolite signature in early pregnancy plasma preceding the onset of SGA offers insight into disease pathogenesis and offers the promise of a robust presymptomatic screening test.

Role of axonal guidance factor netrin-1 in human placental vascular growth

This study investigated the role of netrin-1 in placental vascular development. In vitro rat aortic ring assay and in vivo Matrigel plug assay were conducted to exmaine the effect of netrin-1 on angiogenesis. Human placental microvascular endothelial cells (HPMECs) were isolated and cultured and their viability, migration and tubular formation were studied, in order to examine the effects of netrin-1. The results showed that netrin-1 potently stimulated neovascularization in a mouse Matrigel plug in vivo and the sprouting of endothelial cells in rat aortic rings in vitro. In addition, netrin-1 enhanced the viability, migration and tube formation of HPMECs. Our study suggested that netrin-1 could significantly promote the formation of blood vessels of human placenta and may be a potential target for developing new therapeutic strategies for placental vasculature-related diseases.

A maternal high-fat diet in rat pregnancy reduces growth of the fetus and the placental junctional zone, but not placental labyrinth zone growth

Maternal obesity during pregnancy is often characterized by fetal macrosomia but it can also result in fetal growth restriction in a subset of pregnancies. We hypothesized that mechanisms of this growth restriction may include adverse effects of maternal high fat (HF) intake on placental growth and function. Female rats (100 days old) were time-mated and randomly assigned to either a control (Con) or HF diet ad libitum throughout gestation. At E21, dams were killed; litter size and fetal and placental weights were recorded and maternal and fetal samples collected for further analyses. The HF diet resulted in a 54% increase in maternal body weight gain during gestation. In contrast, male and female fetal weights were reduced in HF pregnancies (P &lt; 0.05), as were the weights of the junctional zone of the placenta (P = 0.013), whereas labyrinth zone weights were unaffected. The HF diet increased maternal and fetal plasma leptin levels (P &lt; 0.05), but maternal and fetal insulin and fetal glucose levels were unaffected. Labyrinthine expression of PPARγ and total VEGFa mRNA, both markers of placental vascular development, were unaffected by consumption of the HF diet in placentas of male and female fetuses. Furthermore, maternal HF nutrition did not alter phosphorylated protein levels of either mammalian target of rapamycin or its downstream signaling factor eIF4E binding protein 1 (4E-BP1). These data show that in the rat, maternal HF nutrition results in fetal and placental junctional zone growth restriction, maternal and fetal hyperleptinemia but did not alter gene expression of markers of placental vascular development.

Angiogenic Factors and Preeclampsia

Preeclampsia, a hypertensive disorder peculiar to pregnancy, is a systemic syndrome that appears to originate in the placenta and is characterized by widespread maternal endothelial dysfunction. Until recently, the molecular pathogenesis of phenotypic preeclampsia was largely unknown, but recent observations support the hypothesis that altered expression of placental anti-angiogenic factors are responsible for the clinical manifestations of the disease. Soluble Flt1 and soluble endoglin, secreted by the placenta, are increased in the maternal circulation weeks before the onset of preeclampsia. These anti-angiogenic factors produce systemic endothelial dysfunction, resulting in hypertension, proteinuria, and the other systemic manifestations of preeclampsia. The molecular basis for placental dysregulation of these pathogenic factors remains unknown, and as of 2011 the role of angiogenic proteins in early placental vascular development was starting to be explored. The data linking angiogenic factors to preeclampsia have exciting clinical implications, and likely will transform the detection and treatment of preeclampsia.

Uterine Artery Doppler in First-trimester Pregnancy Screening

Uterine artery Doppler velocimetry has revolutionized the investigation of the developing placental vasculature. Abnormal placental vascular development is the basis of common obstetric disorders such as preeclampsia and intrauterine growth restriction. Uterine artery Doppler velocimetry by itself or in combination with other biochemical markers seems to be an effective first-trimester screening tool for preeclampsia and in particular early-onset preeclampsia. The diagnostic accuracy although statistically significant, is not as high for the prediction of intrauterine growth restriction unrelated to preeclampsia. In the future, first-trimester prophylaxis using antiplatelet agents in Doppler identified high-risk groups could suppress the development of these disorders.

Vascular Biology of the Placenta

Abstract The placenta is an organ that connects the developing fetus to the uterine wall, thereby allowing nutrient uptake, waste elimination, and gas exchange via the mother’s blood supply. Proper vascular development in the placenta is fundamental to ensuring a healthy fetus and successful pregnancy. This book provides an up-to-date summary and synthesis of knowledge regarding placental vascular biology and discusses the relevance of this vascular bed to the functions of the human placenta. Table of Contents: Introduction / Placental Blood Circulation / Structure of the Placenta / Cell Types of the Placenta / Oxygen Tension and Placental Vascular Development / Vasculogenesis and Angiogenesis of Human Placenta / Angiogenic Factors / Vasoactivators and Placental Vasoactivity / Lymphatic Phenotypic Characteristics of the Human Placenta / Placental Tissue and Cord Blood Stem Cells / Summary / Acknowledgment / References

Maternal obesity and overnutrition alter fetal growth rate and cotyledonary vascularity and angiogenic factor expression in the ewe

In pregnant sheep, maternal:fetal exchange occurs across placentomes composed of placental cotyledonary and uterine caruncular tissues. Recently, we reported that fetal weights of obese (OB) ewes [fed a diet of 150% of National Research Council (NRC) recommendations] were approximately 30% greater than those of control (C) ewes (fed a diet 100% of NRC recommendations) at midgestation (MG), but fetal weights were similar in late gestation (LG). Transplacental nutrient exchange is dependent on placental blood flow, which itself is dependent on placental vascularity. The current study investigated whether the observed initial faster and subsequent slower fetal growth rate of OB compared with C was associated with changes in cotyledonary vascularity and expression of angiogenic factors (vascular endothelial growth factor, fibroblast growth factor-2, placental growth factor, angiopoietin-1 and -2). Cotyledonary arteriole diameters were markedly greater (P < 0.05) in OB than C ewes at MG, but while arteriole diameter of C ewes increased (P < 0.05) from MG to LG, they remained unchanged in OB ewes. Cotyledonary arterial angiogenic factors mRNA and protein expression were lower (P < 0.05) in OB than C ewes at MG and remained low from MG to LG. In contrast, mRNA levels of angiogenic factors in C ewes declined from high levels at MG to reach those of OB ewes by LG. The increase in cotyledonary arteriole diameter in early to MG may function to accelerate fetal growth rate in OB ewes, while the decreased cotyledonary arterial angiogenic factors from MG-LG may function to protect the fetus from excessive placental vascular development, increased maternal nutrient delivery, and excessive weight gain.

Placental development during early pregnancy in sheep: vascular growth and expression of angiogenic factors in maternal placenta

Placental vascular development (angiogenesis) is critical for placental function and thus for normal embryonic/fetal growth and development. Specific environmental factors or use of assisted reproductive techniques may result in poor placental angiogenesis, which may contribute to embryonic losses and/or fetal growth retardation. Uterine tissues were collected on days 14, 16, 18, 20, 22, 24, 26, 28, and 30 after mating and on day 10 after estrus (nonpregnant controls) to determine vascular development and expression of several factors involved in the regulation of angiogenesis in the endometrium. Compared with controls, several measurements of endometrial vascularity increased (P<0.001) including vascular labeling index (LI; proportion of proliferating cells), the tissue area occupied by capillaries, area per capillary (capillary size), total capillary circumference per unit of tissue area, and expression of factor VIII (marker of endothelial cells), but capillary number decreased (P<0.001). Compared with controls, mRNA for placental growth factor, vascular endothelial growth factor receptors, angiopoietins (ANGPT) 1 and 2, ANGPT receptor TEK, endothelial nitric oxide synthase, and hypoxia-inducible factor 1alpha increased (P<0.05) during early pregnancy. Vascular LI was positively correlated (P<0.05) with several measurements of vascularity and with mRNA expression of angiogenic factors. These data indicate that endometrial angiogenesis, manifested by increased vascularity and increased expression of several factors involved in the regulation of angiogenesis, is initiated very early in pregnancy. This more complete description of early placental angiogenesis may provide the foundation for determining whether placental vascular development is altered in compromised pregnancies.

Placental Vasculature in Health and Disease

Both angiogenesis and vasculogenesis occur during normal placental development. Additionally, the placenta undergoes a process of vascular mimicry (also referred to as pseudo-vasculogenesis) where the placental cytotrophoblasts that invade the spiral arteries convert from an epithelial to an endothelial phenotype during normal pregnancy. Failure of placental angiogenesis and pseudo-vasculogenesis during placental development has been linked to the pathogenesis of preeclampsia and related disorders such as intrauterine growth restriction. This review discusses placental vascular development during health and in disease with a focus on accumulating recent evidence that the maternal clinical syndrome of preeclampsia may be due to the result of excess antiangiogenic factors liberated by the diseased placenta.

Secretion of Angiogenic Growth Factors by Villous Cytotrophoblast and Extravillous Trophoblast in Early Human Pregnancy

Angiogenesis is a key feature of placental and uterine development in early pregnancy. We hypothesized that trophoblast cells produce angiogenic growth factors, and that expression differs between villous cytotrophoblast (CTB) and extravillous trophoblast (EVT) cells. Fourteen angiogenic growth factors were measured by multiplex growth factor analysis or ELISA in tissue culture supernatants from EVT and CTB from pregnancies at 8–10 and 12–14 weeks' gestation. Gestational age and cell type differences were observed. EVT and CTB are major producers of angiogenic growth factors that likely contribute to placental vascular development and spiral artery remodeling.