Expression and Function of Placenta Growth

REVIEW ARTICLE Expression and Function of Placenta Growth Factor: Implications for Abnormal Placentation Donald S. Torry, PhD, Debashree Mukherjea, B...
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REVIEW ARTICLE

Expression and Function of Placenta Growth Factor: Implications for Abnormal Placentation Donald S. Torry, PhD, Debashree Mukherjea, BS, Juan Arroyo, BS, and Ronald J. Torry, PhD OBJECTIVE: Essential requirements for successful gestation include the coordinated growth and diferentiation of the placenta and the development of a functional placental vasculature. However, relatively little is known aboutfactors that are responsiblefor regulating thesefunctions. One angiogenicgrowthfactor that might be involved in regulating both vascular endothelial cell and trophoblastfunction is placental growth factor (PGF). METHODS: Current published reports were surveyed and our own work was reviewed to highlight the expression, function, and potential significance of PGF at the human maternal-fetal interface. RESULTS: PGF is highly expressed in trophoblasts during normal pregnancy, and its expression is significantly decreased in preeclampsia, an obstetric complication presumed to be associated with placental bed hypoxia and ischemia. In agreement with this, in vitro trophoblast expression of PGF can be down-regulated by low oxygen tension. The cognate receptorfor PGF, fins-like tyrosine kinase receptor, is expressed on trophoblasts as well as vascular endothelial cells, suggesting that it has autocrine and paracrine functions. Accordingly, PGF can regulate proliferation in first trimester trophoblasts, apoptosis in term trophoblasts, and it can directly or indirectly regulate vascular growth, maturation, and permeability. CONCLUSION: Many obstetric complications, most notably preeclampsia, are associated with aberrant

trophoblastfunction and inadequate or dysfunctional vasculature within the developing placenta. The ability

of PGF to influence trophoblast and vascular endothelial cells provides clear impetusforfurther studies to investigate the biological and dinical significance of PGF in normal and abnormal human pregnancies. (J Soc Gynecol Investig 2003;10:178-88) Copyright C 2003 by the Societyfor Gynecologic Investigation. KEY WORDS: Trophoblast, PGF, angiogenesis, preeclampsia, hypoxia, placentation.

uccessful placentation requires intimate and well-coordinated associations between placental trophoblast development or function and tissue neovascularization. The factors responsible for the initiation and coordination of these processes are not well understood.' Recent studies have confirmed the intuitive requirement for adequate angiogenesis during placentation,2 and some lethal gene knockout studies have documented that specific loss of placental vascularity is a From the Department of Medical Microbiology and Immunology and Obstetrics and Gynecology, Southern Illinois University School of Medicine, Springfield, Illinois; and College of Pharmacy and Health Sciences, Drake University, Des Moines, Iowa. Supported in part by the National Institute of Child Health and Human Development (RO1 HD36830) and the American Heart Association - Heartland Affiliate. While this review was in press, another article confirming the relationship of PGF and preeclampsia was published. In this study, serum PGF levels were decreased approximately threefold at a mean gestational age of 341/2 weeks in women diagnosed with preeclampsia (n = 20) versus their nonnotensive, gestational age-matched counterparts (n = 49), and there were no significant differences in placental weights between the groups. Also, significantly lower levels of serum PGF levels were detectable in women prior to clinical onset of preeclampsia. (Taylor RN, Grimnwood J, Taylor RS, McMaster MT, Fisher Sj, North RA. Longitudinal serum concentrations of placental growth factor: Evidence for abnonrmal placental angiogenesis in pathologic pregnancies. Am J Obstet

Gynecol 2003;188:177-22.) Address correspondence reprint requests to: Donald S. Torry, PhI), Department of Medical Microbiology and In-imunology, Southern Illinois University School of Medicine, PO Box 19626, Springfield, IL 62794-9626. Copyright v 2003 by the Society for Gynecologic Investigation. Published by Elsevier Inc.

likely contributing factor in the demise of the embryo.34 Clinically, it is becoming more apparent that dysfunction of the vasculature can contribute to several obstetric complications, although studies are generally lacking in this area. In this review we highlight potential biologic contributions and functions of placental growth factor (PGF), a member of the

vascular endothelial growth factor (VEGF) family of angiogenic growth factors, in pregnancy. High-level PGF expression in normal trophoblasts has made it a particularly intriguing protein that may have key autocrine roles in trophoblast function as well as paracrine roles in vascular growth at the maternal-fetal interface. We present some of the basic molecular and cellular properties of PGF but focus most of this review on the potential biologic effects of PGF at the maternal-fetal interface and its association with several obstetric complications. Finally, we also discuss some areas of future study that may be important in defining the role of this growth factor in pregnancy. We concentrate here primarily on information concerning human pregnancy but employ animal studies where appropriate to reinforce ideas. The reader is referred to some excellent recent reviews of angiogenesis at the maternal-fetal interface and the role of oxygen in influencing placental vessel formation and 1171 -5576/03/$30.00 doi: 1(0.101 6/S 1()71-5576(0)3)10(1)(48-0

Roles of PGF in

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Figure 1. The cDNA structure of the human PGF isoforms. Exons 1-5 and 7 (open boxes) are present in all isoforms of PGF. Exon 6, which encodes a heparin-binding domain (stippled box), is present in PGF-210 and PGF-4.13 An extra 216-nucleotide sequence between exons 4 and 5 (shladed box) is present in PGF-312 and PGF-4.13 (Data derived from references 10, 12, and 13. See reference section for complete citation of each of these three references.)

trophoblast function,6-9 which are beyond the scope of this review.

MOLECULAR AND CELLULAR FEATURES OF PGF AND ITS RECEPTORS PGF Gene The human PGF gene lies on chromosome 14q24-3 110 and is comprised of seven exons. PGF gene sequence is well conserved in various mammals that have been studied, and homologous genes are thought to exist in avian, amphibian, and insect genomes, suggesting that it may have conserved functions and may not be restricted to mammalian reproduction.10 PGF protein is a member of the cysteine-knot family of growth factors and has significant amino acid homology with VEGF.1' Similar to VEGF, PGF exhibits four different isoforms as a result of alternative splicing of a single PGF primary transcript (Figure 1)i1012"13 PGF-1 consists of six exons, whereas PGF-2 contains the same six exons plus an additional exon (exon 6) that encodes a heparin-binding domain.'1214 PGF-3 is comprised of the same exons as PGF-1 plus an additional 216 nucleotides encoding a 72-amino acid sequence insert between exons 4 and 5.12 Recently, we have shown that human trophoblast can produce a novel isoform, PGF-4, which consists of the same sequence as PGF-3 with the addition of exon 6.'3 Absence of the heparin-binding domain (exon 6) causes PGF-1 and PGF-3 to exist primarily as diffusible forms, whereas inclusion of the heparin-binding domain in PGF-2 and PGF-4 keeps them mainly membrane-associated forms. 12"4 All four isoforms of PGF mRNA are produced by human trophoblast and umbilical vein endothelial cells.'3

PGF Receptors Receptors for PGF include the fins-like tyrosine kinase (flt-1) receptor and the neuropilin-1 (NP-1) receptor. PGF does not bind to the kinase insert domain-containing receptor (KDR), which is a receptor for VEGF.' 516 The flt-1 receptor exists either in a membrane-bound or soluble form (sflt-1). Membrane-bound flt-1 is a homodimeric tyrosine kinase receptor that possesses structural homology with the platelet-derived

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Figure 2. Human PGF receptors: NP-1 receptor, the flt-1 receptor, and the sflt-1 receptor. NP-1 is a transmembrane non-tyrosine kinase receptor composed of two domains homologous to domain III of complement component Clr and Cis (CUB domains), two domains that are homologous to the C1 and C2 domains of coagulation factors V and VIII, and an MAM (A5, mu) domain.33 The flt-1 receptor is a homodimenic tyrosine kinase receptor that consists of seven immunoglobulin-like domains in the extracellular region, a single transmembrane region, and a consensus tyrosine kinase domain in the intracellular domain.i7 The soluble flt-1 receptor consists of six immunoglobulin-like domains and is produced by alternative splicing of the flt-1 gene.27 Other abbreviations as in text. (Data derived from references 17, 27, 33. See reference section for complete citation of these three references.)

growth factor (PDGF) receptor.'7 Flt-1 consists of seven immunoglobulin-like domains in the extracellular domain, a single transmembrane region, and a consensus split tyrosine kinase domain in the intracellular region (Figure 2). This receptor is expressed in a number of cells, including vascular endothelial cells,'7 trophoblasts,'8-20 vascular smooth muscle cells,2' and monocytes. 22- Modeling studies suggest that PGF-1 forms extensive contacts through side chain interactions within the second extracellular immunoglobulin-like domain of flt-1. The flt-1 receptor also binds VEGF, and the overall structure of PGF-1 and its binding characteristics to flt-1 are generally quite similar to those noted for VEGF." The biologic importance of this receptor has been reinforced by murine flt-1deletion experiments, which show that flt-1 is required for embryonic vasculogenesis and angiogenesis.23 Other studies have shown that flt-1 modulates pathologic anglogenesis.24 The soluble flt-1 receptor consists of six immunoglobulinlike domains and is produced by altemative splicing of the flt-1 gene (see Figure 2). This product contains a unique extension of 31 amino acids in the C-terminal end and binds VEGF and PGF with high affinity.2t This receptor was originally identified in human umbilical vein endothelial cells (HUVECs), but high levels have been detected in both villous and extravillous trophoblast.26'27 Soluble fit-1 has been shown to have antagonistic properties and can suppress the biologic effects of PGF and VEGFi.2829 The ability of sflt-1 to bind free VEGF in the sera of normal pregnant women has been documented,97'311 and hypoxia can up-regulate trophoblast expression of silt'1.31 Although this suggests that regulation of angiogenesis by PGF, VEGF, or both can be modulated by sflt-1, the physiologic importance of sflt-1 in regulating vascular growth and perme-

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ability at the human maternal fetal interface has not yet been fully explored. The NP-1 receptor is a previously characterized receptor for the semaphorin-collapsin family of proteins and is important in the guidance of growing neuronal axons.32'33 NP-1 is a transmembrane non-tyrosine kinase receptor composed of two complement-like (CUB) domains, two domains homologous to the coagulation factors V and VIII, and one MAM (meprin, A5, mu) domain33 (Figure 2). This receptor is known to bind VEGF 165 and PGF-2 in a heparin-dependent manner.32 NP-1 is expressed on endothelial cells,34 and its critical importance in developmental angiogenesis,35'36 wound angiogenesis,37 ischemic brain angiogenesis,38 and tumor angiogenesis39 is known. However, the role of NP-1 in regulating human placental vascularity is not known. Similarly, the mechanism of NP-1-mediated angiogenesis is not clear, because VEGF 165 and PGF-2 binding to NP-1 does not seem to directly effect endothelial cell proliferation in vitro.40 To our knowledge, expression of NP-1 in human trophoblast has not yet been documented, but the ability of NP-1 to regulate VEGF and possibly PGF signal transduction cascades41'42 clearly suggests that it should be investigated.

PGF Expression Patterns Under normal physiologic conditions, prominent PGF expression is remarkably restricted to the placenta,12"443 and this restricted expression was initially responsible for its name. Within the placenta, expression is abundant in villous cytotrophoblasts and syncytiotrophoblasts.44-47 At the cellular level it is now appreciated that PGF is also expressed to a high degree in human umbilical vein endothelial cells,' 18 penicytes, and microvascular endothelial cells,48 and to some degree in thyroid, uterine natural killer cells, erythroblastic cells, normal human bone marrow, and cultured keratinocytes, among 43

others.49

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Although high levels of PGF expression are relatively restricted to the placenta in normal situations, PGF expression has been noted in several other tissues in pathologic situations. Most notably, PGF tends to be expressed in tumors exhibiting substantial levels of angiogenesis. PGF mRNA was found to be expressed in 91% of human hypervascular renal cell carcinoma tissues but not in the adjacent normal kidney tissues; two hypovascular carcinoma tissues did not express PGF mRNA.3 PGF expression was found to be high in all primary and metastatic melanoma cell lines but was absent in normal melanocytes.54 In primary brain tumors, PGF mRNA was expressed in all hypervascular tumors studied but only in approximately one third of hypovascular tumors.5 A subset of vascularized human meningiomas express PGF.56 Aside from tumor samples, PGF is induced transiently in migrating human keratinocytes during wound healing.? PGF RNA levels have been shown to be up-regulated by hyperoxia in a mouse retinal vaso-obliteration model,7 which is similar to that seen in patients with proliferative diabetic retinopathy.8 Collectively, these studies suggest that PGF expression is

inducible in many cell types and appears to be associated with areas undergoing angiogenesis.

Regulation of PGF Expression Currently, the best-studied regulators of PGF expression include oxygen tension and cytokines. Hypoxia is a potent stimulus for increasing VEGF expression.59 Much like VEGF,60 the effects of hypoxia on PGF gene expression appear to be tissue dependent. For instance, we18 and others31'61'62 have shown that hypoxia decreases PGF expression in trophoblast cells. In contrast, hypoxia increases PGF expression in cultured fibroblasts63 and glioma cells.55 PGF mRNA expression is increased in ischemic cardiomyocytes ofnormal mice.64 Conversely, hyperoxemia increases baseline expression of PGF in trophoblast31 and in ganglion cells of the retina.57 The molecular explanation(s) for the apparent cell-type-specific effects of oxygen tension on PGF gene expression is (are) not known. In addition to oxygen tension, it is likely that PGF expression might also be regulated by cytokines. PGF mRNA and protein is up-regulated in normal keratinocytes in vitro after treatment with cytokines present at wound sites, such as epithelial growth factor, transforming growth factor-ao, transforming growth factor-, or interleukin (IL)-6. In contrast, IL-lot and tumor necrosis factor-ct had no effect on PGF mRNA induction.52 Many of these same cytokines are expressed at the maternal-fetal interface during pregnancy; however, the ability of cytokines to regulate, positively or negatively, the endogenous expression of PGF in normal trophoblast is not known.

PGF/PGF Receptor Signaling in Trophoblasts We have shown that binding of PGF to flt-1 activates different signal transduction pathways in cultured HUVECs than those induced in cultured primary term trophoblasts.F' Exogenous PGF significantly induces the stress-activated protein kinase

(SAPK) pathways, JNK (c-jun-N-terminal kinase), and p38, with only slight activation of the extracellular-regulated kinase (ERK 1 and 2) pathways in normal term trophoblasts. In contrast, treatment of HUVECs with exogenous PGF led to the strong activation of the ERK pathways with little activation of the SAPK pathways.6D These results suggest that there are cell-type-specific downstream regulators in the signaling cascade of flt-1/PGF. This might explain some of the divergent signal transduction results previously noted in other cell lines that overexpress flt_1.66

BIOLOGIC FUNCTIONS OF PGF It is becoming increasingly evident that PGF may directly or indirectly modulate several key vascular and trophoblast events during placentation. These include angiogenesis or vasculogenesis, vascular maturation and stabilization, vascular permeability, and endothelial cell and trophoblast survival.

Roles of PGF PGE in Pregnancy

PGF and Trophoblast Function and Survival Several early studies documented expression of flt-i receptor in trophoblasts.'8-20 The presence of this receptor in trophoblasts coupled with the high-level expression of PGF by trophoblasts suggests an autocrine function for this growth factor. Importantly, exogenous PGF stimulates proliferation of firsttrimester extravillous trophoblast (EVT), suggesting that this growth factor and its receptor play a role in the growth and development of the placenta.67 Induction of the SAPK pathways in human trophoblasts by PGF provided the first clues to an autocrine function of PGF in normal term trophoblasts. The SAPK pathways regulate apoptosis in many different cell types,68 which led to experiments to determine whether PGF could influence apoptotic events in trophoblasts. Exogenous PGF can protect trophoblasts from growth factor withdrawal-induced apoptosis, but it is not able to protect trophoblasts from apoptosis induced by the proinflammatory cytokines, tumor necrosis factor-a-, and ,y-interferon.F In support of this, inhibition of PGF binding to flt-i increases spontaneous apoptosis rates in cultured trophoblasts by approximately fivefold.47 The ability of PGF to regulate trophoblast apoptosis in vitro raises the possibility that PGF contnbutes to successful placentation by inhibiting vascular and trophoblast apoptosis during gestation. Circumstantial evidence supports this hypothesis in that increased levels of trophoblast apoptosis are noted during preeclampsia,69-71 which coincides with decreased PGF expression.72-75 It is likely that PGF could also influence differentiation in at least a subset of trophoblasts because inhibition of flt-i ligand binding reduced expression of alpha-1-integrin, a differentiation marker that correlates with decreased invasiveness.47

PGF and Angiogenesis The PGF angiogenesis literature appears, at first, to be contradictory. Some studies suggest that PGF-1 may have a direct, pro-angiogenic effect,76 whereas others demonstrate an antiangiogenic effect of PGF-177 More recent studies have demonstrated that, given the tissue microenvironment and the specific PGF isoform used, PGF may promote or inhibit anglogenesis.

The direct role of PGF in promoting angiogenesis is complicated because different isoforms of PGF bind different receptors with different affinities, and they readily form homodimers with themselves and heterodimers with VEGF. Indeed, PGF-1 preferentially forms intracellular heterodimers with VEGF in cells that produce both growth factors.78 Binding studies have shown that PGF homodimers can bind flt-i but not KDR (or Flk-l, the murine homologue of human KDR),"D'16 whereas VEGF/PGF heterodimers bind and activate KDR.78 Although the KDR receptor is thought to mediate the angiogenic effects of VEGF,79 expression of flt-i in angiogenesis is mandatory for normal angiogenesis associated with development.80 More recent studies have shown that only the extracellular domain of flt-i is needed for normal angiogenesis,1781 suggesting that flt-i may influence angio-

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genesis indirectly by acting as a decoy receptor and modulating VEGF-KDR interactions. Regardless of the mechanism, flt-i has been shown to be important in the pathologic vascular growth associated with tumors,24 and it is up-regulated in the vessels of the heart after infarction.82 The direct effect of PGF on endothelial cell proliferation in vitro is complicated by technical differences between studies (reviewed in ref 46). Although some studies suggest that exceedingly high concentrations of PGF homodimers are needed to induce endothelial cell proliferation in vitro,78'83 other studies provide a compelling rationale that PGF can influence angiogenesis directly. For instance, Ziche et al76 were the first to show PGF-1 to be directly angiogenic both in vitro and in vivo. Some have shown that PGF-1 and PGF-232 and PGF-VEGF heterodimers78 induce endothelial cell migration, a key step in branching angiogenesis. PGF potentiates the mitogenic and chemotactic effects of subthreshold concentrations of VEGF," and the basic residues of PGF-2 increase the bioavailability, and hence angiogenic effects, of endogenous VEGF by displacing it from the extracellular matrix.84 Heterodimers of PGF-VEGF exist naturally,83 and they can bind to and induce phosphorylation of KDR,78 the receptor that mediates the mitogenic activity of VEGF.79 However, others have shown that the heterodimers are weak angiogenic agents,78'83 and this has led to the hypothesis that flt-i is a decoy receptor for VEGF whereby PGF occupies the flt-i receptors displacing available VEGF to the KDR receptor. Therefore, PGF-1 may serve as a negative regulator of VEGF angiogenesis by forming VEGF-PGF heterodimers that are functionally ineffective inducers of angiogenesis.77 Overexpression of PGF-1 in tumor cells showed that PGF preferentially formed heterodimers with VEGF such that nearly all the VEGF produced by the cells was complexed with PGF. These heterodimers, as well as PGF homodimers, were unable to induce endothelial cell chemotaxis, KDR activation, cell shape changes, or angiogenesis in a comeal assay. Functionally, tumor cells that overexpress PGF-1 showed delayed growth after injection into murine hosts because of reduced neovascularization.77 Importantly, the inhibitory effects of PGF on various VEGF-dependent processes of angiogenesis required that both factors be coexpressed in the same cell. When added together, but not as heterodimers, PGF-1 did not inhibit (or potentiate) VEGF-induced comeal angiogenesis.77 Applied to the placenta, these findings would support the role of PGF in vascularization, because different cell types in the placenta produce VEGF and PGF, and little heterodimerization is thought to occur.44 The spatial and temporal association between angiogenesis and increased endogenous PGF expression during proliferative '8 6 cutaneous wound healing, 5264 retinopathy, -' and tumor growth"'64 provide further support for PGF as a regulator of tissue vascularity in pathologic conditions. Overexpression of murine PGF in mouse skin produced a substantial increase in the number, size, and branching of dermal vasculature.87 PGF knockout mice are fertile and produce relatively normal offP o inplacentation c a minor role spring, 64 suggesting that thtPFplays

investig Vol. 10, No. 4, May 2003 182 J1 Soc Gynecol Investig and normal developmental angiogenesis. However, extrapolating PGF gene knockout studies in mice to humans is complicated because of significant differences in placentation. In addition, it is not known, given the multitude of other angiogenic growth factors and transcription factors in the placenta, 188 whether increased activity of other factors compensated for the PGF deficiency in these mice. Indeed, VEGF protein expression was 45% greater in PGF-null embryos compared with wild-type embryos.64 The effect of acute PGF gene inactivation on placentation is not known. Nevertheless, lack of PGF expression inhibited reactive angiogenesis associated with pathologic conditions such as ischemic limb, retinal, and cardiac tissue; wound healing; and tumor growth.64 In wildtype mice, PGF expression was significantly up-regulated under these pathologic conditions, each characterized by compensatory vascular growth.64 Similarly, inhibition of Flt-t activity with neutralizing monoclonal antibody produced a dose-dependent decrease in vascular growth in the corneal assay, ischemic retinal, and tumor models of pathologic angiogenesis.89 Collectively, these results suggest that endogenous PGF contributes to angiogenesis by amplifying the effects of VEGF during pathologic conditions.64 Exogenous PGF stimulated pathologic angiogenesis associated with myocardial ischemia and hind-limb ischemia, whereas adenoviral PGF overexpression facilitated the formation of mature, stable, nonleaky blood vessels in the skin.89 Clearly, the factors regulating angiogenesis in the placenta are not known.1 In addition, there is an emerging realization that the microenvironment, characterized by interactions between developing blood vessels, the interstitium, and the tissue itself, ultimately modulate the angiogenic process.90 However, similarities between the invasiveness of tumor cells and human trophoblasts during embryo implantation9' as well as morphologic similarities in the resulting vasculature92 suggest that placental angiogenesis mimics that of certain types of pathologic angiogenesis. Thus, PGF may play an important role in compensatory vascular growth during placentation.

PGF and Vascular Maturation and Stability Establishment of competent vasculature starts with the growth of naked endothelial tubes and concludes with the maturation and stabilization, or arterialization, of certain vessels. The maturation-stabilization steps are mediated by extravascular cells such that, once they are covered with smooth muscle cell actin-positive cells, the endothelial cell tubes do not regress in the absence of an angiogenic signal.93 Unique mechanisms regulate angiogenesis and arteriogenesis.94 For instance, although VEGF is a potent inducer of angiogenesis, neither endogenous nor exogenous VEGF directly regulates arteriogenesis.95 Arteniogenesis is enhanced by monocyte chemotactic protein-l9z confirming that mononuclear cell infiltration contributes significantly to stabilization of existing neovasculature.96 In that PGF is a known chemoattractant for monocytes and macrophages,97 it is reasonable to suspect that the impaired arteriogenesis observed in PGF-null mice was also

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associated with a significant reduction in macrophage infiltration.64 Direct support for PGF's role in vascular stabilization was confirmed when exogenous PGF promoted the formation of persistent, mature, nonleaky blood vessels and enhanced macrophage recruitment into the site of vascular growth.89 PGF stimulates vascular smooth muscle cell proliferation under certain conditions in vitro.98 These results suggest that PGF can function directly or indirectly to stabilize new vasculature. However, the role ofPGF in stabilizing placental vasculature is not known.

PGF and Vascular Permeability PGF may also play an important role in regulating vascular permeability within the placenta. PGF knockout mice demonstrated reduced vascular leakage after challenge by wounding, delayed hypersensitivity (Arthus reaction), and mustard oil-induced inflammation.99 Overexpression of PGF in keratinocytes resulted in a significant increase in vascularity and permeability.87 These results suggest that PGF may, directly or indirectly, promote vascular permeability under pathologic conditions. Increased vessel permeability results in the deposition of a fibrin-rich extracellular matrix which promotes angiogenesis. 100

PGF and Endothelial Cell Apoptosis Given the structural and physiologic relationships with VEGF,64 PGF may also play an important anti-apoptotic role in vivo. Indeed, acting through the flt-l receptor, exogenous PGF plus VEGF or PGF-VEGF heterodimers significantly inhibited apoptosis in endothelial cells from PGF knockout mice.64 Others have shown that abrupt withdrawal of PGF-2 expression produced increased apoptosis in vascular endothelial cells and macrophages.'0'

CLINICAL CONSIDERATIONS The predominant expression of PGF by trophoblasts and its down-regulation by hypoxia has spurred a number of studies to address the clinical significance of PGF in pregnancy. The rationale for most of these studies is straightforward, as many common and significant complications of human pregnancy are associated with uteroplacental vascular dysfunction.' Although it is difficult to determine whether aberrant vascular formation or function is the direct cause or effect in many of these obstetric complications, the vascular pathophysiologies associated with the complications provide clear impetus for further study.

PGF and Normal Pregnancy Serum PGF protein73 and placental mRNA expression' demonstrate a trimodal expression pattern during normal pregnancy. The first cross-sectional study of maternal serum showed low PGF protein levels from approximately 5 to 15 weeks' gestation.73 Serum PGF levels increase -dramatically from approximately 15 weeks to 26 weeks. The increase in serum PGF levels at approximately 15 weeks noted in this study seems to correlate well with the time at which blood

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Roles of PGF in Pregnancy Table 1. Maternal Blood PGF Levels in Clinically Established Preeclampsia

Study Torry et a173

Reuvekamp et a174 Livingston et a172 Livingston et a175 Helske et al121

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