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REVIEW |
Centre for Trophoblast Research and Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK1 Centre for Trophoblast Research and Department of Obstetrics and Gynaecology, and the National Institute of Health Research Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, CB2 2SW, UK and2 Academic Department of Obstetrics and Gynaecology, Institute for Women's Health, University College London, WC1E 6HX, London, UK
Correspondence should be addressed to G J Burton; Email: gjb2{at}cam.ac.uk
This paper is one of four papers that form part of a special Focus Issue section on Vascular Function in Female Reproduction. The Guest Editor for this section was H N Jabbour, Edinburgh, UK.
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Abstract |
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Introduction |
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550 km in length and 15 m2 in surface area (Burton & Jauniaux 1995). This network is essential for effective materno-fetal exchange, but also plays a key mechanistic role in the elaboration of the placental villous tree. Vasculogenesis and subsequent angiogenesis are therefore of pivotal importance in placental development, and it is imperative that they are appropriately regulated. Failure to do so can lead to intrauterine fetal growth restriction and poor obstetric outcome. |
Morphological aspects of vascular development |
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The endothelial cells of the human placenta are of the non-fenestrated type, and adjacent cells are linked by junctional complexes comprising both tight and adherens junctions (Heinrich et al. 1976, Jones & Fox 1991). Besides stabilizing the capillary wall, these complexes regulate paracellular solute transport. Molecular studies have revealed that during the first trimester the tight junctions lack occludin and claudin-1 and -2, whereas the adherens junctions lack plakoglobin, molecules that are typically associated with mature forms of the respective junctions (Leach et al. 2002). This immaturity suggests that at this stage of gestation the capillaries are in a plastic state, suitable for remodeling, and are also highly permeable.
By 4 weeks pc (6 weeks post-LMP), capillary profiles can be observed peripherally in the villous core in close proximity to the trophoblast, along with some larger vessel profiles in the central region (Fig. 1). By now the capillaries are connected via the developing umbilical cord to the fetal heart, and to the vascular plexus of the yolk sac. The fetal heart has been beating for 1 week (from day 35 post-LMP), but an effective villous circulation is not established for a further 2 weeks (Jauniaux et al. 1991b). The delay in achieving flow appears to be due to the fact that most of the erythrocytes present within the early villous capillaries are nucleated, and so not readily deformable. They therefore impose a high resistance on the circulation, and this is reflected in the raised pulsatility index of the umbilical arterial waveforms at this stage of pregnancy. At the end of the first trimester, the resistance falls as the proportion of nucleated erythrocytes decreases rapidly.
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3–4 (Fig. 2b), although there is wide variation between individual placentas (Mayhew 2002). Indeed, disproportionate growth of the capillaries has long been thought to lead to the obtrusion of capillary loops from the villous surface, raising the trophoblastic epithelium in a blister-like fashion and initiating the formation of a new terminal villus (Kaufmann et al. 1985, 2004). The acceleration in capillary growth seen at around 25 weeks correlates closely with the formation of terminal villi in the same placental samples (Jackson et al. 1992), and so provides indirect support for this theory. However, estimation of capillary length using stereological techniques cannot distinguish between capillary elongation, with subsequent looping, and sprouting, for it is based only on counts of capillary profiles. Recently, three-dimensional reconstructions of images captured by confocal microscopy have revealed terminal villi forming in mature placentas by the obtrusion of both capillary loops and blind-ending sprouts (Jirkovska et al. 2008). It is now clear that at least two mechanisms for terminal villus formation operate, but each has angiogenesis as its driving force.
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Molecular regulation of vasculogenesis and angiogenesis in the human placenta |
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Vascular endothelial growth factor
Vascular endothelial growth factor (VEGFA) is considered to be the most important factor promoting the differentiation of mesenchymal cells in the villous core into hemangioblastic stem cells. It acts via two receptors, FLT1 and KDR. VEGFA is expressed intensely by the cytotrophoblast cells in the first few weeks of pregnancy, whereas the hemangiogenic cell cords show the strongest immunoreactivity for KDR. Mice in which VEGFA, or KDR, is knocked-out fail to initiate vasculogenesis (Shalaby et al. 1995, Carmeliet et al. 1996, Ferrara et al. 1996). Paracrine signaling may thus explain the proximity of the hemoangioblastic clusters to the trophoblastic epithelium. Later, expression of VEGFA in the cytotrophoblast cells wanes, whereas the villous macrophages and mesenchymal cells become strongly immunopositive. VEGFA is a powerful endothelial cell mitogen, and this switch may support angiogenic remodeling of the early vessels, stimulating the formation of a capillary network within the mesenchymal villus core (Demir et al. 2004).
Placental growth factor
The VEGF family also contains placental growth factor (PGF, also called PlGF), which, as its name suggests, is highly expressed in the trophoblast. Its function is less clear than that of VEGFA. PGF binds to FLT1 but not KDR, and so may influence angiogenesis rather than vasculogenesis. However, PGF and FLT1 play a role in the mobilization of mesenchymal endothelial precursor cells that contribute to vasculogenesis (Li et al. 2006). In the past it has been viewed as a competitive inhibitor of VEGFA, for studies suggested it is a relatively weak mitogen for endothelial cells. However, in vivo data indicate that it may be as potent as VEGFA in stimulating new vessel growth (Ziche et al. 1997).
Longitudinal measurements of the placental concentrations of VEGFA and PGF throughout pregnancy are not possible, and so levels in the maternal plasma have been taken as a surrogate index of the placental angiogenic stimulus. This is complicated by the fact that the trophoblast secretes soluble receptors for both growth factors into the maternal circulation, influencing their bioavailability profoundly (Charnock Jones et al. 2004). Nonetheless, the general pattern observed is that maternal levels of total VEGFA rise gradually throughout pregnancy, whereas there is a marked increase in free PGF between 28 and 32 weeks of gestation. These profiles are altered in complicated pregnancies, for in cases of preeclampsia, maternal circulating levels of free PGF are suppressed.
Angiopoietins
The angiopoietins are another important family of growth factors that regulate angiogenesis in the placenta and elsewhere. Angiopoietin-1 and -2 are both ligands for the TIE2 tyrosine kinase receptor. ANG1-mediated phosphorylation of TIE2 promotes endothelial cell survival, and the recruitment of pericytes and smooth muscle cells that help to stabilize newly formed capillaries. In contrast, ANG2 is thought to act as a competitive inhibitor of ANG1, destabilizing the vessels and so rendering them more susceptible to the angiogenic stimulus of VEGFA or other growth factors. In the absence of a stimulatory growth factor, the vessels regress. ANG1 and 2 have been localized to the villous trophoblast from early gestation onwards, with RT-PCR data suggesting that the ratio of their mRNAs changes in favour of ANG1 as pregnancy advances (Charnock-Jones 2002, Seval et al. 2008). The TIE2 receptor is present on villous endothelial cells, and also the trophoblast, although its influence on trophoblast biology is unknown.
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Oxygen as a regulator of placental angiogenesis |
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It is now widely accepted that the human placenta develops under low-oxygen concentrations during the first trimester in the absence of a significant maternal circulation (Jauniaux et al. 2000), conditions that would be expected to support vasculogenesis and angiogenesis. In the absence of experimental manipulations, it is difficult to determine how critical this environment is, but there is indirect evidence that it may be crucial. First, increased numbers of hemangiogenic cords are present in early villi from pregnancies complicated by maternal anemia (Kadyrov et al. 1998), when the oxygen concentration in the developing placenta might be expected to be even lower than normal. Second, comparisons between villi located in the central and peripheral regions of the placenta indicate that hyperoxia has the opposite effect. Ultrasonography has shown that when maternal blood flow to the placenta commences at the end of the first trimester, it does so in a peripheral–central fashion (Jauniaux et al. 2003). Consequently, oxygen concentrations will be higher in the periphery, and increased levels of oxidative stress in villi sampled from this site provide supportive evidence that this is the case. These villi are notably either avascular or contain degenerate capillaries, consistent with the withdrawal of VEGFA support secondary to a hyperoxic environment (Alon et al. 1995). Similar changes are seen in placentas retained in utero in cases of missed miscarriage, when onset of the maternal circulation is premature and widespread throughout the placenta (Jauniaux et al. 2003). Again there is evidence of increased oxidative stress, particularly in the syncytiotrophoblast that is a prime source of VEGFA. There is a negative correlation between the volume of the fetal capillaries in the villi and the time for which the placenta has been retained after fetal death, indicating progressive regression of the capillary network under these hyperoxic conditions (Hempstock et al. 2003b).
At the end of the first trimester, oxygen concentrations within the placental intervillous space normally rise threefold (Jauniaux et al. 2000). Then, from 16 weeks they gradually fall, from 60 to 40 mmHg at term, as placental and fetal oxygen consumption increase (Soothill et al. 1986). The latter figures were obtained by aspiration of intervillous blood through the chorionic plate at the time of cordocentesis; and while providing an important guide as to placental oxygenation, they do not take into account regional variations in oxygen concentrations that may play an important role in regulating villus morphogenesis. Thus, when maternal blood is delivered into the placenta from the spiral arteries, it is directed to the center of a placental lobule, from which it then percolates peripherally. An oxygen gradient would therefore be expected across the lobule, but this cannot be confirmed by direct measurements using current technologies for practical and ethical reasons. However, measurements of antioxidant enzyme expression and activity in villous tissues sampled from different sites within lobules support this hypothesis (Hempstock et al. 2003a). It is also notable that dilated capillary sinusoids and vasculosyncytial membranes are more prominent in the peripheral regions of a lobule, where oxygen concentrations are predicted to be the lowest (Fox 1964, Critchley & Burton 1987).
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Sprouting versus non-sprouting angiogenesis |
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The evidence emerging from the three-dimensional reconstructions of Jirkovská et al. (2008) challenges this hypothesis, for they regularly observed terminal villi in mature placentas containing blind-ending capillary sprouts. The concept that branching angiogenesis continues beyond week 24 is supported indirectly by data from high-altitude pregnancies, in which the terminal villi are shorter and more clustered, suggesting increased capillary branching during the second half of pregnancy when the terminal villi are principally formed (Ali et al. 1996). Interestingly, the proportion of capillaries associated with pericytes is reduced at altitude compared with sea-level controls, conferring greater plasticity in a similar fashion as during the first trimester (Zhang et al. 2002). In addition, the finding that endothelial junctional complexes are immature in terminal villi again suggests these capillary networks are plastic even in late pregnancy (Leach 2002).
As discussed earlier, the bioavailability of these growth factors at the villous level during pregnancy is difficult to predict due to the secretion of soluble receptors. It is likely that the rate and mode of angiogenesis will not be dictated by one factor alone, but rather by a complex integration of signaling mechanisms of which oxygen and growth factors are two contributors. Indeed, a quantitative analysis of villous vascularization across the first to second trimester transition did not reveal any sudden changes in response to the rising oxygen levels (Jauniaux et al. 1991a). Although there may be changes in the pattern of placental angiogenesis during gestation, the hypothesis that there is a clear-cut dichotomous shift from branching to non-branching angiogenesis mid-pregnancy no longer appears tenable. Further studies quantifying capillary sprouting throughout gestation are required to resolve the issue.
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Mechanical factors in the regulation of placental angiogenesis |
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Shear stress may be an important factor in the larger vessels of stem and intermediate villi, but at the level of terminal villi, the rate of flow is unlikely to be sufficient to generate significant forces. Cyclic strain is probably more important at these sites, especially given the acute changes in direction that must occur within the capillary plexus. This may explain the location of the dilated sinusoids at the apices of capillary loops (Burton & Tham 1992). The observation that the capillary sinusoids are capable of expansion/compression dependent upon the pressure differential between the maternal and fetal circulations indicates that the capillary walls have elastic properties (Karimu & Burton 1994). The pressure differential is likely to rise during gestation as the fetal heart matures, and so one might envisage a continually increasing distending force being applied. This will be resisted by the complement of intermediate fibres within the endothelial cells, and also by the composition of the extracellular matrix and the presence of encircling collagen fibres. The interaction between mechanical forces and local growth factors in sculpting vasculosyncytial membranes deserves further investigation, for these sites are of key importance to materno-fetal exchange.
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Dysregulation of placental angiogenesis in pathological pregnancies |
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Hyperoxia is postulated to have the opposite effect, leading to reduced capillary branching and impoverished terminal villi (Kingdom & Kaufmann 1997). It is argued that these changes will reduce oxygen extraction from the intervillous space, so promoting further hyperoxia. While this may be true it is a rather circular argument, and the initial precipitating cause of the placental vascular maldevelopment is not clear.
Hypoxia and hyperoxia are relative terms, and as discussed earlier the pattern of maternal blood flow through the lobule means that villi in different regions will experience different oxygen concentrations. The terms therefore have to be qualified according to the location and the stage of gestation that is being considered.
Our recent research indicates that the constancy of the prevailing oxygen concentration may be a more critical factor than the absolute value. We have hypothesized that the deficient conversion of the maternal spiral arteries associated with the majority of pregnancy complications increases the risk of spontaneous vasoconstriction of the arteries, and hence predisposes the placenta to ischemia–reperfusion-type injury. When normal placental explants are exposed to hypoxia–reoxygenation in vitro, high levels of oxidative stress are generated in the trophoblast and endothelial cells, mimicking the changes seen in preeclampsia (Hung et al. 2001). We have observed the same distribution of oxidative stress in placentas from uncomplicated pregnancies following labour and vaginal delivery, while it is absent from those delivered by caesarean section (Fig. 4; Cindrova-Davies et al. 2007).
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Conclusion |
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Declaration of interest |
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Funding |
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Received March 7, 2009
First decision April 15, 2009
Accepted May 21, 2009
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  H N Jabbour Vascular function in female reproduction Reproduction, December 1, 2009; 138(6): 867 - 868. [Full Text] [PDF]
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| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
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Abstract
Introduction
