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Biology of Reproduction 64, 1033-1040 (2001)
© 2001 Society for the Study of Reproduction, Inc.

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Angiogenesis in the Placenta1

Lawrence P. Reynolds2,a,b, and Dale A. Redmera

a Department of Animal & Range Sciences, and b Cell Biology Center, North Dakota State University, Fargo, North Dakota 58105-5727


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PLACENTAL CIRCULATION AND FETAL...
 PLACENTAL BLOOD FLOW AND...
 FACTORS THAT REGULATE PLACENTAL...
 REGULATION OF ENDOMETRIAL VEGF...
 CONCLUDING REMARKS
 REFERENCES
 
The mammalian placenta is the organ through which respiratory gases, nutrients, and wastes are exchanged between the maternal and fetal systems. Thus, transplacental exchange provides for all the metabolic demands of fetal growth and development. The rate of transplacental exchange depends primarily on the rates of uterine (maternal placental) and umbilical (fetal placental) blood flows. 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. The rates of placental blood flow, in turn, are dependent on placental vascularization, and placental angiogenesis is therefore critical for the successful development of viable, healthy offspring. Recent studies, including gene knockouts in mice, indicate that the vascular endothelial growth factors represent a major class of placental angiogenic factors. Other angiogenic factors, such as the fibroblast growth factors or perhaps the angiopoietins, also may play important roles in placental vascularization. In addition, recent observations suggest that these angiogenic factors interact with the local vasodilator nitric oxide to coordinate placental angiogenesis and blood flow. In the future, regulators of angiogenesis that are currently being developed may provide novel and powerful methods to ensure positive outcomes for most pregnancies.

The [umbilical] vessels join on the uterus like the roots of plants and through them the embryo receives its nourishment. Aristotle, On the Generation of Animals, ca. 340 B.C.

female reproductive tract, placenta, pregnancy, uterus


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PLACENTAL CIRCULATION AND FETAL...
 PLACENTAL BLOOD FLOW AND...
 FACTORS THAT REGULATE PLACENTAL...
 REGULATION OF ENDOMETRIAL VEGF...
 CONCLUDING REMARKS
 REFERENCES
 
In 1937, Mossman [1] stated "The normal mammalian placenta is an apposition or fusion of the fetal membranes to the uterine mucosa for the purpose of physiological exchange." Even though it was coined more than 60 yr ago, his definition of the mammalian placenta still provides an excellent working definition that is broad enough to cover all of the diverse types of mammalian placentas [2, 3]. Mossman reminds us firstly that the placenta involves close contact or intimate association and secondly that this intimate contact involves tissues from two organisms, namely the fetal membranes and the maternal uterine mucosa or endometrium. Lastly, Mossman's definition defines the primary purpose of the placenta: physiological exchange.

In fact, all of the respiratory gases, nutrients, and wastes that are exchanged between the maternal and fetal systems are transported via the placenta [2, 4, 5]. Thus, the importance of transplacental exchange in supplying the metabolic substrates required for fetal growth is apparent and has long been recognized [2, 4, 5–8].


   PLACENTAL CIRCULATION AND FETAL GROWTH AND DEVELOPMENT
TOP
 ABSTRACT
 INTRODUCTION
 PLACENTAL CIRCULATION AND FETAL...
PLACENTAL BLOOD FLOW AND...
 FACTORS THAT REGULATE PLACENTAL...
 REGULATION OF ENDOMETRIAL VEGF...
 CONCLUDING REMARKS
 REFERENCES
 
In mammals, most embryonic loss (>=30% of fertilized ova in most mammalian species and perhaps over 50% in humans) occurs during early pregnancy [9, 10]. The reason early pregnancy is such a critical period of gestation probably is because of the major developmental events that take place, including embryonic organogenesis as well as formation of the placenta, a process known as placentation [1, 3, 6, 11–14].

Placentation includes extensive angiogenesis in maternal and fetal placental tissues, accompanied by a marked increase in uterine and umbilical blood flows (Fig. 1) [5, 6, 15–19]. These events provide the developing conceptus with an optimal uterine environment to meet its metabolic demands and probably also influence the rate of physiological exchange between the maternal and fetal systems later in pregnancy [5, 6, 20]. Indeed, reduced placental vascular development and increased vascular resistance have been associated with early embryonic mortality [21, 22].



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  		FIG. 1. Histochemical staining of endometrial (caruncular) capillaries from A) nonpregnant (Day 12 postestrus) and B) early pregnant (Day 30 postmating) ewes. Note in early pregnant compared with nonpregnant ewes (B vs. A) the dramatic increase in the number of endometrial capillaries (arrows) and formation of a subepithelial capillary plexus (*). Total endometrial microvascular volume of the gravid uterine horn (i.e., the uterine horn containing the embryo proper) had increased twofold by Day 24 after mating; the nongravid horn exhibited a similar increase by Day 30 (C). Note that the nongravid uterine horn did not contain fetal membranes (FM) until Day 30. In B, note the binucleate cell within the fetal membranes (lower right portion of micrograph). Data were adapted from Reynolds and Redmer [18]; original magnification was x400 for both micrographs.

Establishment of functional fetal and placental circulations are some of the earliest events during embryonic/placental development [2, 23, 24]. It has been shown that the large increase in transplacental exchange, which supports the exponential increase in fetal growth during the last half of gestation, depends primarily on the dramatic growth of the placental vascular beds and the resultant large increases in uterine and umbilical blood flows [5, 25]. Factors that affect fetal growth, such as maternal genotype, increased numbers of fetuses, maternal undernutrition, maternal age, parity, or environmental heat or cold stress, typically have similar effects on placental size and also are associated with reduced rates of fetal oxygen and nutrient uptakes and placental blood flow [5]. 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 [26–28]. Thus, factors that influence placental vascular development and function will have a dramatic impact on fetal growth and development, and thereby on neonatal survival and growth [5, 25, 29–31].


   PLACENTAL BLOOD FLOW AND ANGIOGENESIS
TOP
 ABSTRACT
 INTRODUCTION
 PLACENTAL CIRCULATION AND FETAL...
 PLACENTAL BLOOD FLOW AND...
FACTORS THAT REGULATE PLACENTAL...
 REGULATION OF ENDOMETRIAL VEGF...
 CONCLUDING REMARKS
 REFERENCES
 
Because the placenta's primary role is to provide for physiological exchange, the importance of the placental circulation also has long been recognized and is exemplified by the close relationships among fetal weight, placental size, and uterine and umbilical blood flows during normal pregnancies in many mammalian species [2, 4–6, 19, 32]. Uterine and umbilical blood flows that represent the circulation to the maternal and fetal portions of the placenta, respectively, increase exponentially throughout gestation, essentially keeping pace with fetal growth [5, 19, 25].

In his chapter in the Handbook of Physiology, Meschia [25] states:

In the adult organism local variations of blood flow at constant arterial and venous pressure are generally the result of local vasodilatation or vasoconstriction. The large increase of blood flow to the uterus during pregnancy, however, results primarily from the formation and growth of the placental vascular bed.

Vascular growth, or angiogenesis, is indeed a major component of the increase in placental blood flow throughout gestation [5, 6, 19, 25, 32, 33].

Several early investigators provided histological descriptions of placental vascular growth in several mammalian species [6, 33, 34]. Our laboratories provided not only a histological but also a quantitative description of maternal placental (endometrial) angiogenesis during early pregnancy (Days 12–30 after mating) in sheep that have a gestation length of ~145 days (Fig. 1) [18]. By Day 24 after mating, structural vascular volume of the endometrium exhibits a twofold increase in the gravid uterine horn (i.e., the uterine horn containing the embryo proper; Fig. 1). The endometrium of the nongravid uterine horn also exhibits angiogenesis but not until Day 30 after mating in association with the initial presence of fetal membranes in this nongravid horn [18].

Vascular density of maternal placental tissues continues to increase slowly throughout gestation (Fig. 2) [35]. In contrast, vascular density of the fetal placental cotyledons remains relatively constant through midgestation and increases dramatically during the last third of gestation in association with dramatic fetal growth (Fig. 2) [33, 35]. These patterns of placental angiogenesis coincide with the dramatic increases that have been reported for uterine and umbilical blood flows, and also with data indicating that umbilical blood flow increases more rapidly than uterine blood flow during the last third of gestation [5, 36–38].



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  		FIG. 2. Microvascular density of caruncular (maternal) and cotyledonary (fetal) placental tissues from Day 40 until the end of gestation in ewes. This figure is taken from Reynolds and Redmer [5] and is adapted from the data of Stegeman [35] that were reported originally as arbitrary density units.


   FACTORS THAT REGULATE PLACENTAL ANGIOGENESIS
TOP
 ABSTRACT
 INTRODUCTION
 PLACENTAL CIRCULATION AND FETAL...
 PLACENTAL BLOOD FLOW AND...
 FACTORS THAT REGULATE PLACENTAL...
REGULATION OF ENDOMETRIAL VEGF...
 CONCLUDING REMARKS
 REFERENCES
 
Angiogenesis refers to the formation of new vascular beds, and is a critical process for normal tissue growth and development [39–41]. Although numerous factors have been implicated in angiogenesis, recent observations, including gene knockout studies in mice, have led to the identification of the major factors regulating the angiogenic process, including those that occur during placental vascularization.

These angiogenic factors include the vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and the angiopoietin (ANG) protein families, as well as their respective receptors [40, 42–45]. That recent studies have suggested that VEGF and FGF are major angiogenic growth factors of the placenta is not surprising because these two families of proteins probably account for most of the heparin-binding angiogenic activity produced by both ovarian [46] and placental [47–51] tissues.

The VEGFs are specific stimulators of vascular permeability, as well as vascular endothelial cell protease production and migration, all of which are critical components of the angiogenic process [39–42, 46]. Vascular endothelial growth factor also stimulate angiogenesis in a variety of in vivo and in vitro models [52–54]. Based on a host of in vitro and in vivo studies, it appears that VEGFs are primary regulators of angiogenesis in normal and pathological processes, including luteal growth, wound healing, coronary ischemia, and tumor growth [42, 55].

Recent evidence also has implicated VEGF in fetal and placental angiogenesis. For example, VEGF or VEGF receptor (VEGFR) mRNA are associated with the angiogenesis that occurs during development of brain ventricles, kidney glomeruli, and placental tissues during late pregnancy in mice [43, 56]. Breier et al. [43] localized VEGF mRNA to brain and glomerular vasculature in neonates as well as adults. Similarly, VEGF and VEGFR mRNA and protein are present in human fetal and placental tissues [57–62]. We and others have shown that VEGF is produced by sheep placental tissues throughout gestation (Fig. 3) [51, 63–66]. Recently, we have shown tissue and cell-specific patterns of expression of placental VEGF (Figs. 3 and 4) [51, 64–66].



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  		FIG. 3. Expression of VEGF and bFGF mRNA in sheep placental tissues from A) early and B) late pregnancy. A) CAR, Caruncular endometrium that contains the maternal placental villi; ICAR, intercaruncular endometrium that contains the endometrial glands; FM, fetal membranes (chorioallantois); COT, cotyledon, which contains the fetal placental villi; and ICOT, intercotyledonary fetal membranes. Superscripts along the X-axis indicate days sampled for each tissue (see days above figure). Note that whereas the CAR and ICAR are present even in the nonpregnant uterus, the FM does not differentiate into the COT and ICOT regions until after Day 30. In B, placentome refers to maternal CAR plus fetal COT, because these tissues are interdigitated and thus cannot be separated cleanly in late pregnancy. These data were obtained by ribonuclease protection assay and are expressed in proportion to the tissue that exhibited the greatest expression; total number of ewes was 25 and 12 in A and B, respectively

For example, during early pregnancy, expression of VEGF mRNA is greater in fetal placental compared with maternal placental (endometrial) tissues (Fig. 3A). In contrast, basic FGF (bFGF) mRNA is greatest in endometrial compared with fetal placental tissues (Fig. 3A). In late pregnancy, VEGF mRNA remains high in the placentome and intercotyledonary fetal membranes, whereas bFGF mRNA is greatest in the intercotyledonary fetal membranes (Fig. 3B). During early pregnancy, VEGF protein localizes to the developing cotyledonary microvasculature (Fig. 4A). During late pregnancy, however, VEGF protein is found primarily in the microvessels of the maternal caruncular villi, with only a portion of the fetal cotyledonary arterioles exhibiting VEGF protein (Fig. 4B).



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  		FIG. 4. Immunohistochemical localization of VEGF in sheep placental tissues from A) early pregnancy and B) late pregnancy. Note that during early pregnancy (A) VEGF localizes primarily to the vasculature of the developing fetal cotyledon (arrows), but little VEGF was present in the maternal placental (endometrial) tissues (lower right corner). During late pregnancy (B), VEGF localizes primarily to the capillaries (arrows) of the maternal placental villi (MV) and to arterioles (*) within the fetal placental villi (FV). Note in B that the fetal villi contain binucleate cells (arrowhead)

Gene knockout studies have provided convincing evidence for a central role of VEGF in fetal and placental angiogenesis. In mice, homozygous knockouts of the genes for VEGFRs (VEGFR-1 [also known as flt-1] or VEGFR-2 [KDR or flk-1]) led to defects in fetal and placental vasculogenesis (the initial formation of the vasculature) and angiogenesis resulting in embryonic death by about Day 8 of pregnancy (length of pregnancy {approx}20 days) [67, 68]. These defects were primarily reflected by abnormal vascular formation, organization, and patterning, as well as abnormal endothelial morphology. Similarly, homozygous gene knockouts for VEGF itself were lethal by about Day 11 of pregnancy, and these embryos exhibited dramatic cardiovascular defects, such as delayed or abnormal development of the heart, aorta, major vessels, and extraembryonic vasculature, including the yolk sac and placenta [69, 70]. Surprisingly, heterozygous VEGF-gene knockout embryos that still expressed VEGF but at reduced levels exhibited similar defects in fetal and placental angiogenesis and also died by about Days 11–12 of gestation [69, 70]. These authors therefore concluded that not only was fetal and placental angiogenesis absolutely dependent on VEGF, but that threshold levels of VEGF must be achieved for normal vascular development to occur.

The FGFs also are potent angiogenic factors in vivo and in vitro and, in addition, stimulate proliferation of both uterine arterial and fetal placental arterial endothelial cells [39, 40, 71, 72]. The FGFs are unique among the major angiogenic growth factors in that they are pleiotropic and influence not only angiogenesis but also various other developmental and differentiated functions [73]. For example, although bFGF (FGF-2) is thought to be a major ovarian angiogenic factor, it also stimulates follicular and luteal cell growth and luteal progesterone production [46, 74, 75]. The FGFs also may promote cell survival in a variety of cell types [46, 76, 77]. Moreover, the FGFs have been shown to stimulate differentiation of the embryonic germ layers, especially embryonic mesoderm [78, 79]. We and others have shown that bFGF is produced by fetal and maternal placental tissues throughout gestation [50, 51, 80–82]. We have also shown tissue-specific patterns of expression of placental bFGF mRNA during early (Fig. 3A) and late (Fig. 3B) gestation [81, 82]. These studies have led us and others to propose a role for bFGF in amplifying the angiogenic response of the endometrium to the presence of the embryonic tissues as well as in the differentiation of vascular and nonvascular tissues derived from mesoderm [46, 80, 83, 84].

In addition to their role in placental angiogenesis, both VEGF and bFGF also may be involved in regulating placental blood flow. For example, in ovariectomized rats or ewes, endometrial expression of VEGF and bFGF mRNA is strongly upregulated within a few hours after estrogen treatment, in association with a dramatic increase in uterine vascularization and blood flow [19, 85–87]. Both VEGF and bFGF have been implicated in stimulating endothelial production of nitric oxide (NO), a major local vasodilator that has been shown to mediate estrogen-induced increases in uterine blood flow [71, 88–92]. Likewise, NO can regulate expression of VEGF and bFGF [93–95].

Additional angiogenic factors likely are important for placental vascular development. For example, based on gene-knockout studies, the ANGs also have been shown to be major angiogenic factors and regulate vascular growth and development both negatively and positively [43, 96–98]. As seen for VEGF, both ANG1 and ANG2 appear to be vascular-specific growth factors because their principle receptor, Tie2, is present primarily on endothelial cells [43, 99]. Angiopoietin-2 is a natural Tie2 antagonist that appears to be involved primarily in vascular regression and thus has been suggested as a modulator of vascular growth and perhaps even an important antiangiogenic factor [99, 100]. Angiopoietin-1 is a Tie2 agonist that has been shown to be critical for embryonic vascular development because embryos lacking ANG1 exhibit numerous cardiovascular defects and die by midgestation [43, 96]. Although ANG1 does not stimulate endothelial cell proliferation, it promotes microvascular organization and endothelial cell survival [98, 101–104]. In addition, like VEGF, ANG1 appears to be produced primarily by periendothelial cells and thus may act as a partner to VEGF in the angiogenic process [98, 100]. Although Tie2 has been localized to fetal and maternal placental vascular endothelial cells [105], suggesting a role for the ANGs in placental angiogenesis, to our knowledge the expression of ANG1 in placental tissues has not been evaluated.


   REGULATION OF ENDOMETRIAL VEGF AND bFGF EXPRESSION
TOP
 ABSTRACT
 INTRODUCTION
 PLACENTAL CIRCULATION AND FETAL...
 PLACENTAL BLOOD FLOW AND...
 FACTORS THAT REGULATE PLACENTAL...
 REGULATION OF ENDOMETRIAL VEGF...
CONCLUDING REMARKS
 REFERENCES
 
As mentioned above, endometrial expression of VEGF and bFGF mRNA is upregulated 3- to 10-fold in ovariectomized ewes within a few hours after estrogen treatment [86, 87]. This strong upregulation of VEGF and bFGF mRNA is associated with increased endometrial VEGF and bFGF protein expression and with dramatic increases (5- to 10-fold) in uterine blood flow as well as endometrial microvascular volume, which is a quantitative measure of angiogenesis [19, 86, 87].

Both VEGF and bFGF can stimulate endothelial production of NO by a variety of endothelial cells, including those from the uterine and fetal placental arteries [71, 89, 106]. In addition, the uterine blood flow response to estrogen is probably mediated largely by NO, which can stimulate production of VEGF and bFGF [19, 93, 94]. Moreover, endometrial VEGF is present primarily in arteriolar vascular smooth muscle and capillary pericytes, which is consistent with its localization to periendothelial cells in ovarian and other tissues [46, 86]. Because endometrial microvascular estrogen receptors (ER) also localize to the vascular smooth muscle (Fig. 5A), we investigated the expression of ER protein in endometrial blood vessels in response to steroid treatment and also during early pregnancy.



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  		FIG. 5. A) Estrogen receptor protein in an endometrial arteriole from an ovariectomized (OVX), estrogen plus progesterone-treated ewe. Note that vascular smooth muscle exhibits intense nuclear staining for ER (arrows), whereas the endothelial cells exhibit only the hematoxylin counterstain (arrowheads). Two endometrial glands (lower right corner) also exhibit nuclear staining for ER. The two lower figures (B and C) represent quantitative data (the percentage of the total arteriolar nuclear area occupied by ER protein, based on immunohistochemical staining and image analysis) for B) OVX, steroid-treated ewes; and C) nonpregnant (NP) and early pregnant (PG) ewes. In B, OVX + estrogen (OVX+E) was greater (P < 0.05) than OVX, OVX + progesterone (OVX+P), or OVX + E + P or OVX + P + E. In C, NP on Day 14 of the estrous cycle (NP14) was less (P < 0.05) than NP on Day 12 (NP12) or any day of early pregnancy (PG12 through PG24). CAR, Caruncular; ICAR, intercaruncular; luminal, near the uterine lumen; deep, near the endometrial-myometrial border. For details of the procedures used, see Zheng et al. [113]

Estrogen receptor protein was upregulated in endometrial vascular smooth muscle by estrogen treatment of ovariectomized ewes (Fig. 5B) [107]. In addition, ER protein was maintained in endometrial vascular smooth muscle during early pregnancy, in contrast with nonpregnant ewes in which vascular ER was dramatically reduced by Day 14 of the estrous cycle (Fig. 5C). In both of these studies, the vascular ER localized almost exclusively to the vascular smooth muscle of the endometrial arterioles. Recently, we have shown that endothelial NO synthase localizes to endothelial cells of endometrial arterioles and capillaries in ovariectomized, steroid-treated sheep and also in early pregnant sheep [108]. These observations confirm other reports in sheep and humans [92, 109, 110] and indicate that estrogen may mediate its effects on endothelial NO production indirectly via the vascular smooth muscle. In addition, because endometrial ER also localize to the glandular epithelium, which produces bFGF, we and others have suggested a role for estrogen-stimulated bFGF secretion in regulating endometrial vascular function [86, 111].

Based on these observations, we have developed a working model to describe the paracrine interaction between endometrial endothelial cells that express NO synthase and periendothelial cells and glandular epithelium that express VEGF and bFGF, respectively, and also contain the ERs (Fig. 6). Although glandular epithelium probably secretes bFGF in a lumenal direction, we are also suggesting basal secretion of bFGF, which seems reasonable because the endometrial glands are well supplied with microvessels [18]. The paracrine interaction described by this model would provide a positive feedback loop to stimulate endometrial angiogenesis and blood flow, thereby ensuring adequate placental vascularization and perfusion (Fig. 6). This model also emphasizes the importance of evaluating the cellular location of the multiple factors involved in placental angiogenesis.



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  		FIG. 6. Working model for regulation of endometrial (maternal placental) vascular function by VEGF and bFGF in sheep. This model is based on numerous studies from our laboratories and those of others in which the major players have been not only quantified but also localized to specific tissues and cell types. In this model, estrogen binds to its nuclear receptors in the vascular smooth muscle cells of the endometrial arterioles and in the glandular epithelial cells, to stimulate VEGF and bFGF production, respectively. Both VEGF and bFGF act on the endothelial cells to stimulate angiogenesis (endothelial proliferation, migration, and permeability) as well as NO production. The NO acts back on the vascular smooth muscle to induce vasodilation and also potentially to stimulate VEGF production further, thereby establishing a positive feedback loop to maximize placental angiogenesis and blood flow. A similar positive feedback loop may exist between the endometrial capillary endothelial cells and pericytes, because pericytes express VEGF and are from the vascular smooth muscle cell lineage. The schematic of the arteriole was adapted from Rhodin [114]


   CONCLUDING REMARKS
TOP
 ABSTRACT
 INTRODUCTION
 PLACENTAL CIRCULATION AND FETAL...
 PLACENTAL BLOOD FLOW AND...
 FACTORS THAT REGULATE PLACENTAL...
 REGULATION OF ENDOMETRIAL VEGF...
 CONCLUDING REMARKS
REFERENCES
 
As mentioned above, adequate placental angiogenesis is critical for the establishment of the placental circulation and thus for normal fetal growth and development. Whether reduced placental vascularity is secondary to placental insufficiency, or conversely, whether inadequate placental vascularization is a cause of placental dysfunction is not known at present. However, there is no doubt that inadequate placental vascular development, secondary to reduced VEGF or VEGFR expression, is a lethal embryonic defect [67–70]. It therefore seems reasonable to suggest that inappropriate placental expression of angiogenic factors may contribute to placental vascular defects and placental dysfunction and thereby be an important cause of infertility and fetal growth retardation. With the recent spate of clinical work on regulators of angiogenesis [112], these observations lead us to believe that regulation of placental angiogenesis could become a novel and powerful method for ensuring positive outcomes for most pregnancies.


   ACKNOWLEDGMENTS
 
We thank our collaborators and colleagues, Drs. Russell Anthony, Stephen Ford, Anna Grazul-Bilska, Derek Killilea, Ronald Magness, and Robert Moor; and our current and former students: Mr. Daniel Arnold, Ms. Holly Berginski, Dr. Vinayak Doraiswamy, Dr. Mary Lynn Johnson, Ms. Dana Millaway, and Dr. Jing Zheng, each of whom has made invaluable contributions to our work in this area. Their efforts, collaborations, insights, and discussions are greatly appreciated.


   FOOTNOTES
 
First decision: 26 April 2000.

1 We gratefully acknowledge the financial support of the U.S. National Institutes of Health, the U.S. National Science Foundation, and the North Dakota Agricultural Experiment Station. Back

2 Correspondence. FAX: 701 231 7590; larry_reynolds{at}ndsu.nodak.edu Back

Accepted: October 30, 2000.

Received: April 3, 2000.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PLACENTAL CIRCULATION AND FETAL...
 PLACENTAL BLOOD FLOW AND...
 FACTORS THAT REGULATE PLACENTAL...
 REGULATION OF ENDOMETRIAL VEGF...
 CONCLUDING REMARKS
 REFERENCES
 

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J. M. Wallace, R. P. Aitken, J. S. Milne, and W. W. Hay Jr.
Nutritionally Mediated Placental Growth Restriction in the Growing Adolescent: Consequences for the Fetus
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Maternal Nutrition and Fetal Development
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H. Kwon, S. P. Ford, F. W. Bazer, T. E. Spencer, P. W. Nathanielsz, M. J. Nijland, B. W. Hess, and G. Wu
Maternal Nutrient Restriction Reduces Concentrations of Amino Acids and Polyamines in Ovine Maternal and Fetal Plasma and Fetal Fluids
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A. J Rowe, C. Wulff, and H. M Fraser
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S. A. Soto-Navarro, T. L. Lawler, J. B. Taylor, L. P. Reynolds, J. J. Reed, J. W. Finley, and J. S. Caton
Effect of high-selenium wheat on visceral organ mass, and intestinal cellularity and vascularity in finishing beef steers
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Vascular endothelial growth factor, epidermal growth factor and fibroblast growth factor-4 and -10 stimulate trophoblast plasminogen activator system and metalloproteinase-9
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M. L. Moce, M. A. Santacreu, A. Climent, and A. Blasco
The effect of divergent selection for uterine capacity on fetal and placental development at term in rabbits: Maternal and embryonic genetic effects
J Anim Sci, April 1, 2004; 82(4): 1046 - 1052.
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H. Kwon, G. Wu, C. J. Meininger, F. W. Bazer, and T. E. Spencer
Developmental Changes in Nitric Oxide Synthesis in the Ovine Placenta
Biol Reprod, March 1, 2004; 70(3): 679 - 686.
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Membrane Estrogen Receptor-Dependent Extracellular Signal-Regulated Kinase Pathway Mediates Acute Activation of Endothelial Nitric Oxide Synthase by Estrogen in Uterine Artery Endothelial Cells
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H. Kwon, G. Wu, F. W. Bazer, and T. E. Spencer
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I. Koukoulas, J. Risvanis, R. Douglas-Denton, L. M. Burrell, K. M. Moritz, and E. M. Wintour
Vasopressin Receptor Expression in the Placenta
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D. Thumkeo, J. Keel, T. Ishizaki, M. Hirose, K. Nonomura, H. Oshima, M. Oshima, M. M. Taketo, and S. Narumiya
Targeted Disruption of the Mouse Rho-Associated Kinase 2 Gene Results in Intrauterine Growth Retardation and Fetal Death
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D. S. Torry, D. Mukherjea, J. Arroyo, and R. J. Torry
Expression and Function of Placenta Growth Factor: Implications for Abnormal Placentation
Reproductive Sciences, May 1, 2003; 10(4): 178 - 188.
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H. Kwon, T. E. Spencer, F. W. Bazer, and G. Wu
Developmental Changes of Amino Acids in Ovine Fetal Fluids
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A. Tokumura, Y. Kanaya, M. Miyake, S. Yamano, M. Irahara, and K. Fukuzawa
Increased Production of Bioactive Lysophosphatidic Acid by Serum Lysophospholipase D in Human Pregnancy
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G. Ambrosini, A. K. Nath, M. R. Sierra-Honigmann, and J. Flores-Riveros
Transcriptional Activation of the Human Leptin Gene in Response to Hypoxia. INVOLVEMENT OF HYPOXIA-INDUCIBLE FACTOR 1
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C. Wulff, H. Wilson, S. E. Dickson, S. J. Wiegand, and H. M. Fraser
Hemochorial Placentation in the Primate: Expression of Vascular Endothelial Growth Factor, Angiopoietins, and Their Receptors Throughout Pregnancy
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