Normal embryonic developmentis dependent upon asufficient oxygen, nutrient and waste exchange through the placenta. Inprimates including humans, this exchange is attained by successful haemochorial placentation which requires the transformation of maternal intramyometrial spiral arterioles by trophoblast invasion to gainuteroplacental circulation,and establishment and maintenance of acompetent fetoplacental vasculature. Thus,trophoblast and endothelial cell differentiation, proliferation and invasion occurring during placentation have to be tightly regulated.This review focuse son the diverse developmental steps during haemochorial placentation in humans and other primates and the possible involvement of angiogenic growth factors (vascular endothelial growth factor(VEGF)and angiopoietins(Ang)) in these processes, high lighting the importance of specific actions of angiogeniclig and–receptor pairs.It is hypothe sized thatVEGF/VEGF-R1and Ang-1/Tiereceptor2 (Tie-2)may regulate trophoblast differentiation and invasion; VEGF/VEGF-R2 and Ang-1/Tie-2 may promotefeto placental vascular development and stabilization; and Ang-2/Tie-2 maybe involved in maternal vascular remodelling.The importance of a tigh tregulation of angiogenic factors and their endogenousantagonists for normal development of the placenta is demonstrated by failure of this system, resulting in abnormal placenta vascularization and trophoblastinvasion associated with intrauterine growth retardationor pre-eclampsia.
In recent years, increasing attention has been drawn to the regulation of angiogenesis during placental development. Not only is the placenta a good model in which to study angiogenesis as a result of its high physiological angiogenic activity, but also there is evidence that failure in the development of a functional vasculature leads to severe conditions such as intrauterine growth retardation of the fetus and pre-eclampsia of the mother. Placentation is a dynamic process in which a number of developmental changes occur. Differentiation and developmental processes may be regulated by changes in gene expression of angiogenic growth factors and their receptors. Thus, during placentation the spatial and temporal changes in gene expression may be studied to begin to reveal the physiological role of angiogenic factors in the regulation of trophoblast growth and differentiation and vascular development. Investigating the processes during placentation is difficult for various reasons. In humans, it is difficult to obtain normal control placentas from intact pregnancies during the second half of gestation. In addition, investigation of the feto-maternal interface and placental bed is complicated but necessary when investigating pathological conditions such as pre-eclampsia. Placenta bed biopsies taken during Caesarean sections require some technical expertise and again collection of appropriate controls in humans is nearly impossible. However, interspecies differences during placentation are marked, and it is essential that these differences are considered when extrapolating physiological, endocrinological, immunological or angiogenic data from the animal to the human situation. This review focuses on the regulation of angiogenesis and placental development in primates because of their similarity in developing an efficient placenta for oxygen and nutrient exchange, the haemochorial placenta. Major developmental steps during placentation in primates are the differentiation of the trophoblast, trophoblast invasion of maternal tissue, remodelling of maternal vasculature to gain a uteroplacental circulation and development of a competent fetoplacental vasculature within the trophoblast. Although these processes are common in primates, the placenta of humans is characterized by deep trophoblast invasion and complete remodelling of maternal vasculature by digestion of upper parts of myometrial spiral arterioles. On the basis of knowledge of similarities and differences during placentation in humans and non human primates,it is aimed to piece together the potential role of angiogenic growth factors in molecular regulation of these diverse developmental steps. This is of particular importance when selecting animal models with which the molecular basis of pathological conditions, such as pre-eclampsia, may be investigated.
Apart from in humans, natural occurring pre-eclampsia is observed only in few primates such as the patas monkey (Erythrocebus patas) (Palmer et al., 1979), a species that is not widely used in reproduction research. Several attempts have been undertaken to induce pre-eclampsia in various species including non-human primates (Douglas, 1976; Combs et al., 1993; Hennessy et al., 1999); however,all of them have failed to mimic the complete clinical picture of the human disease. The main pathomech-anism behind this disorder is believed to be due to incomplete remodelling of maternal spiral arterioles by the invading trophoblast. Only species developing a haemochorial placenta may therefore be affected.Thus, it is of major importance to elucidate physiological and pathological gene expression of angiogenic factors potentially involved in trophoblast growth, invasion and maternal vascular remodelling during primate placentation.
Apart from in humans, natural occurring pre-eclampsia is observed only in few primates such as the patas monkey (Erythrocebus patas) (Palmer et al., 1979), a species that is not widely used in reproduction research. Several attempts have been undertaken to induce pre-eclampsia in various species including non-human primates (Douglas, 1976; Combs et al., 1993; Hennessy et al., 1999); however,all of them have failed to mimic the complete clinical picture of the human disease. The main pathomech-anism behind this disorder is believed to be due to incomplete remodelling of maternal spiral arterioles by the invading trophoblast. Only species developing a haemochorial placenta may therefore be affected.Thus, it is of major importance to elucidate physiological and pathological gene expression of angiogenic factors potentially involved in trophoblast growth, invasion and maternal vascular remodelling during primate placentation.
Comparative placentation in humans and non-human primates
From a macroscopic point of view, primates develop a discoidal placenta which means that the feto-maternal
interaction takes place in a roughly circular area. Whereas most non-human primates have a bi-discoidal
placenta, humans develop a mono-discoidal placenta.In most primates, for example rhesus monkeys, baboons and marmosets, implantation is superficial (Fig. 1a). The blastocyst is simply attached to the uterine epithelium and the conceptus remains within the uterine lumen (Hearn, 1986). It is only in great apes and humans that the blastocyst becomes completely embedded in the endometrium (Fig. 1a), so that interstitial implantation takes place (Hearn, 1986). The simplest form of the fetomaternal interdigitation found in non-primates is the folded trophoblast type. The uterine surface is thrown into numerous undulations. The folding serves to build a high surface area for the exchanges taking place between fetus and mother. By interruption of the parallel folds and formation of arrays of broad palmate branches an even higher surface is created. The so-called trabecularshaped trophoblast type (Fig. 1b) is the feature of primates (Kaufmann and Burton, 1994). The most efficient way for nutrients and oxygen exchange per volume tissue is to increase the surface area of the trophoblast. This is guaranteed by the formation of a tree-like trophoblast type in which trophoblast villi are formed by repeated branching of stem villi into more slender units. This villous-type placenta (Fig. 1c) is found in humans (Kaufmann and Burton, 1994) and in patas monkeys (Palmer et al., 1979). With respect to blood supply, in most species the trophoblast is simply apposed to the uterine epithelium without any or minimal destruction of the maternal tissue (epitheliochorial or endotheliochorial implantation, respectively). Thus, there is no direct contact of maternal blood with fetal tissue. Further invasion leads to erosion of maternal vessels, so that the trophoblast is bathed directly by the mother’s blood (Fig. 1d). This is termed haemochorial placentation, and is typical for most non-human primates and humans. Here, the barrier between the fetal and mother’s blood is very thin, making the exchange of oxygen and nutrients very efficient. A haemomonochorial placenta type develops throughout pregnancy in which the trophoblast consists of the fetal capillaries, interstitial tissue and a monolayer of the syncytiotrophoblast. The depth of trophoblast invasion and maternal vascular remodelling varies among primates; the deepest invasion of the trophoblast with a nearly complete digestion of maternal vessels is found in humans.
From a macroscopic point of view, primates develop a discoidal placenta which means that the feto-maternal
interaction takes place in a roughly circular area. Whereas most non-human primates have a bi-discoidal
placenta, humans develop a mono-discoidal placenta.In most primates, for example rhesus monkeys, baboons and marmosets, implantation is superficial (Fig. 1a). The blastocyst is simply attached to the uterine epithelium and the conceptus remains within the uterine lumen (Hearn, 1986). It is only in great apes and humans that the blastocyst becomes completely embedded in the endometrium (Fig. 1a), so that interstitial implantation takes place (Hearn, 1986). The simplest form of the fetomaternal interdigitation found in non-primates is the folded trophoblast type. The uterine surface is thrown into numerous undulations. The folding serves to build a high surface area for the exchanges taking place between fetus and mother. By interruption of the parallel folds and formation of arrays of broad palmate branches an even higher surface is created. The so-called trabecularshaped trophoblast type (Fig. 1b) is the feature of primates (Kaufmann and Burton, 1994). The most efficient way for nutrients and oxygen exchange per volume tissue is to increase the surface area of the trophoblast. This is guaranteed by the formation of a tree-like trophoblast type in which trophoblast villi are formed by repeated branching of stem villi into more slender units. This villous-type placenta (Fig. 1c) is found in humans (Kaufmann and Burton, 1994) and in patas monkeys (Palmer et al., 1979). With respect to blood supply, in most species the trophoblast is simply apposed to the uterine epithelium without any or minimal destruction of the maternal tissue (epitheliochorial or endotheliochorial implantation, respectively). Thus, there is no direct contact of maternal blood with fetal tissue. Further invasion leads to erosion of maternal vessels, so that the trophoblast is bathed directly by the mother’s blood (Fig. 1d). This is termed haemochorial placentation, and is typical for most non-human primates and humans. Here, the barrier between the fetal and mother’s blood is very thin, making the exchange of oxygen and nutrients very efficient. A haemomonochorial placenta type develops throughout pregnancy in which the trophoblast consists of the fetal capillaries, interstitial tissue and a monolayer of the syncytiotrophoblast. The depth of trophoblast invasion and maternal vascular remodelling varies among primates; the deepest invasion of the trophoblast with a nearly complete digestion of maternal vessels is found in humans.
Placental development
Although the time span of the placentation period differs among primates, the fundamental developmental steps necessary for successful placentation are similar: (1) trophoblast invasion; (2) vascularization of the trophoblast to establish and maintain a fetoplacental vasculature; and (3) subsequent maternal vascular remodelling to gain a uteroplacental circulation. During early placentation the trophoblast differentiates into two compartments, the syncytiotrophoblast and the cytotrophoblast (Fig. 2a). The syncytiotrophoblast invades maternal tissue (Fig. 2b), the depth of invasion depending on the species. Further development leads to penetration of cytotrophoblastic cones into the syncytiotrophoblastic mass (Fig. 2c). First lacunae develop within the syncytiotrophoblast. Further growth and differentiation processes lead to branching of the trophoblast villi and shaping of a placental labyrinth (Fig. 2d).From the extra-embryonic mesenchyme, mesenchymal cores differentiate and grow into the centre of the cytotrophoblast cores. Then endothelial cells differentiate from mesenchymal cells forming the first capillaries of the fetal placenta vasculature. At the same time the beginning of maternal vascular remodelling takes place. By opening of maternal vessels, the placenta labyrinth is filled with maternal blood, flowing around the villous tree. Thus, the haemochorial placenta has developed.
The trophoblast is intrinsically an avascular tissue and so for it to take part in materno-fetal exchange it must develop a functional circulation. Two processes, vasculogenesis and angiogenesis, are involved. Vasculogenesis is defined as the development of new blood vessels from primitive precursor cells, whereas angiogenesis is the development of new vessels from a pre-existing vasculature. Thus, vasculogenesis and angiogenesis are
Although the time span of the placentation period differs among primates, the fundamental developmental steps necessary for successful placentation are similar: (1) trophoblast invasion; (2) vascularization of the trophoblast to establish and maintain a fetoplacental vasculature; and (3) subsequent maternal vascular remodelling to gain a uteroplacental circulation. During early placentation the trophoblast differentiates into two compartments, the syncytiotrophoblast and the cytotrophoblast (Fig. 2a). The syncytiotrophoblast invades maternal tissue (Fig. 2b), the depth of invasion depending on the species. Further development leads to penetration of cytotrophoblastic cones into the syncytiotrophoblastic mass (Fig. 2c). First lacunae develop within the syncytiotrophoblast. Further growth and differentiation processes lead to branching of the trophoblast villi and shaping of a placental labyrinth (Fig. 2d).From the extra-embryonic mesenchyme, mesenchymal cores differentiate and grow into the centre of the cytotrophoblast cores. Then endothelial cells differentiate from mesenchymal cells forming the first capillaries of the fetal placenta vasculature. At the same time the beginning of maternal vascular remodelling takes place. By opening of maternal vessels, the placenta labyrinth is filled with maternal blood, flowing around the villous tree. Thus, the haemochorial placenta has developed.
The trophoblast is intrinsically an avascular tissue and so for it to take part in materno-fetal exchange it must develop a functional circulation. Two processes, vasculogenesis and angiogenesis, are involved. Vasculogenesis is defined as the development of new blood vessels from primitive precursor cells, whereas angiogenesis is the development of new vessels from a pre-existing vasculature. Thus, vasculogenesis and angiogenesis are
both involved in fetal vascular development. Conversion of maternal spiral arterioles associated with angiogenesis differs between non-human primates and humans. In humans, the trophoblast invades deep into the maternal uterine tissue causing complete digestion of the upper parts of maternal spiral arterioles. By the open endings of maternal vessels, maternal blood is released into the placenta labyrinth and flows around the trophoblast villi and is drained by venous sinosoids. A different situation occurs in non-human primates, for example in marmosets, in which the invasion of maternal tissue is less deep. Here, maternal vessels persist throughout pregnancy. However, gaps in the maternal vascular wall are found in increasing number throughout pregnancy, from which the placental labyrinth is filled with maternal blood (Fig. 2d)...Download
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