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REVIEW |
1 School of Veterinary Medicine and Science2 Division of Animal Sciences, University of Nottingham, Sutton Bonington Campus, Loughborough, Leicestershire, LE12 5RD, UK
Correspondence should be addressed to R S Robinson; Email: bob.robinson{at}nottingham.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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Key angiogenic regulators |
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Initial recruitment of thecal vasculature |
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There is remarkably little information regarding how the follicle initially recruits its vascular network. The likely candidate is VEGFA, which is first detected in the granulosa and theca layers of secondary follicles in cows (Yang & Fortune 2007) while ANGPT and FGF2 do not appear in these cells until the antral stages (van Wezel et al. 1995, Hayashi et al. 2004). Furthermore, administration of VEGFA stimulated the development of secondary follicles in cows (Yang & Fortune 2007). While VEGF trap administration in primates reduced the endothelial cell area of secondary follicles and inhibited the formation of antral follicles (Wulff et al. 2002).
However, it is unclear what stimulates VEGFA expression because hypoxia-induced factor 1
(HIF1A) (a transcription factor induced by hypoxia and a potent inducer of VEGFA) was absent from pre-antral follicles (Duncan et al. 2008). It is also unlikely to be gonadotrophins because pre-antral follicle growth is gonadotrophin independent. It could alternatively be an oocyte-derived factor. Both PDGF and FGF2 are present in the oocyte of primordial and primary follicles (van Wezel et al. 1995, Nilsson et al. 2006). Additionally, both factors promote the primordial to primary transition, pre-antral follicular growth and recruitment of theca cells (Nilsson et al. 2006, Matos et al. 2007). However, their effects on theca vascularity are currently unknown.
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Pre-antral follicular vasculature |
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40% of all proliferating cells in the theca are of endothelial origin (Martelli et al. 2009). There were parallel increases in the expression of VEGFA mRNA in both granulosa and theca. Intriguingly, during early pre-antral follicle growth, there was a positive correlation between the degree of proliferation and vascular area (Martelli et al. 2009). From this, it is tempting to speculate that pre-antral follicular selection is based on vascular supply. |
Antral follicle and dominance |
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Neovascularisation is crucial for antral follicle growth, dominance and pre-ovulatory development since numerous studies have shown that anti-angiogenic compounds (e.g. VEGFA trap) reduced the thecal vascularity and consequently severely comprised follicular development (Wulff et al. 2002, Fraser & Duncan 2009). However, whether dominance is achieved by a follicle having a more extensive vasculature and thus receiving greater hormonal support (Zeleznik et al. 1981) remains to be elucidated. This hypothesis is supported by the observation that, during dominant follicle selection, those follicles that were oestrogen-active had vastly greater vascularisation and VEGFA concentrations than their oestrogen-inactive counterparts. This was despite the oestrogen-inactive follicle being larger in diameter (Grazul-Bilska et al. 2007). There is also strong evidence that, shortly after selection, there is a rapid degeneration of the thecal vasculature, once atresia has been initiated in the subordinate follicles (Jiang et al. 2003, Macchiarelli et al. 2006). However, any vascularisation differences are likely to be subtle and its temporal aspect makes it very difficult to prove the original hypothesis definitively. The recent advances in measuring ovarian blood flow have begun to shed more light on this issue. In mares, the follicles that became dominant had an increased blood flow prior to deviation when compared to their subsequent subordinates (Acosta et al. 2004). While a similar study in the cow was less conclusive, there was a rapid reduction in blood flow in subordinate follicles after deviation (Acosta et al. 2005). However, these technologies will enable us to increase our understanding of the regulation of follicular blood flow. It is possible that this will lead to the development of strategies to promote follicular function by manipulating blood flow.
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Regulation of follicular angiogenesis |
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The effects of VEGFA will be further modulated by the co-ordinated action with other angiogenic factors (e.g. ANGPT, PDGF and FGF2). Recently, Greenberg et al. (2008) demonstrated that VEGFA's action was markedly modulated if FGF2 and/or PDGF were present. It has been shown that FGF2 is present in the theca interna layer of antral follicles and in the granulosa, albeit at lower levels. Additionally, FGF2 concentrations increased during the final stages of follicular maturation in cows (van Wezel et al. 1995, Berisha et al. 2000a) and were increased by eCG in gilts (Shimizu et al. 2002). However, no studies have investigated the effects of inhibiting FGF2 at any stage of follicular development and much remains to be elucidated about its role in regulating follicular angiogenesis. While the majority of the studies have focused on pro-angiogenic factors, one anti-angiogenic factor, namely, thrombospondin (TSP) has received some attention. Greenaway et al. (2005) found that TSP1 and its receptor CD36 were present at maximal levels in small antral follicles in the cow. Thereafter, TSP1 concentrations decreased as the antral follicles developed, but were found to be upregulated during atresia in the marmoset (Thomas et al. 2008). Thus, the upregulation of TSP1 might play a key role in follicular atresia by inhibiting angiogenesis. Intriguingly, TSP1 expression was increased by LH in the rat granulosa cells and were present in the early CL (Petrik et al. 2002). This indicates that there is still much to learn about the role of TSP in controlling ovarian angiogenesis.
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Follicle–luteal transition: a period of intense angiogenesis |
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Control of luteal vascularisation |
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1, β1 and β2 as well as nidogen, perlecan and focimatrix), while the ECM associated with the vasculature is principally composed of collagen IV and laminin β2 (Irving-Rodgers et al. 2006). In the pre-ovulatory follicle, there is likely to be a shift away from vascular expansion to vessel maturation and this notion is supported by increases in the ANGPT1:ANGPT2 ratio at this time in cows (Hayashi et al. 2004). Moreover, the injection of ANGPT2 into pre-ovulatory follicles of rhesus monkeys attenuated follicular maturation and prevented ovulation presumably by disrupting pericyte–endothelial cell interactions (Xu & Stouffer 2005). This highlighted the importance of the recruitment of pericytes and/or vSMC during the latter stages of follicular development. These cells, through their contractile properties, are likely to influence the follicular blood flow as well as stabilising the vasculature. Further investigation into how and when these mural cells are recruited during folliculogenesis and in particular the role of PDGF and transforming growth factor β is essential.
LH surge: the initiation of angiogenesis
The LH surge upregulates numerous genes (e.g. cyclo-oxygenase and progesterone receptor) that induce a series of cellular and biochemical processes that culminate in ovulation (Reynolds & Redmer 1999). A number of these events (e.g. breakdown of the basement membrane, immune-like response) play a fundamental role in initiating angiogenesis. LH might also have some direct effects on angiogenesis. For example, follicular FGF2 mRNA and protein concentrations dramatically increase following the LH surge in cows (Berisha et al. 2006, Robinson et al. 2007). At the same time, FGF2 also spatially translocates from thecal endothelial cells to the nucleolus of granulosa cells (Berisha et al. 2006). However, little is known about FGF2 during this time in other species. The limited information that is available, indicates that FGF2 is unaffected by the LH surge in women (Seli et al. 1998) and FGF2 production by human luteinising granulosa cells in vitro remains constant (Phan et al. 2006). The ANGPT2:ANGPT1 ratio in follicles also increases after the LH surge in cows (Shimizu et al. 2007) and macaques (Hazzard et al. 1999) and this may induce the destabilisation of existing vessels. Whether LH can upregulate follicular VEGFA remains unresolved. In most in vitro studies, LH or hCG stimulated VEGFA production by granulosa cells in primates (Martinez-Chequer et al. 2003, van den Driesche et al. 2008) and cows (Schams et al. 2001). However, ex vivo studies have been less conclusive with some showing LH stimulation in primates (Stouffer et al. 2001) and mice (Kim et al. 2009), while others, in cows, showed only small and transient increases (Berisha et al. 2006) or no effect (Robinson et al. 2007). It appears that this effect is similar for the different VEGFA isoforms 121, 165 and 189 (Berisha et al. 2008). Conversely, in pigs, VEGFA concentrations initially decreased in the granulosa layer in response to LH, but increased in the theca layer (Martelli et al. 2006). While the exact regulation of VEGFA by the LH surge remains to be elucidated, it is clear that VEGFA is in abundance in the periovulatory follicle in preparation for the intense angiogenesis that occurs after ovulation.
During the periovulatory period, there is also hyperaemia and increased ovarian blood flow (Acosta et al. 2003). This is probably due to increased nitric oxide production (Mitsube et al. 2002) following the upregulation of endothelial nitric oxide synthase (eNOS) and inducible NOS in the thecal vasculature (Zackrisson et al. 1996). However, this is more likely to be an E2 mediated upregulation rather than the effect of LH since E2 is a potent, rapid stimulator of eNOS in endothelial cells (Kim et al. 2008). VEGFA also plays a role since it stimulates vascular permeability. Increases in blood flow would normally result in increased supply of oxygen to the tissue, however, HIF1A is upregulated in the periovulatory follicle of marmosets (Duncan et al. 2008) and in the collapsed follicle of pigs (Boonyaprakob et al. 2005) which suggests that the tissue is hypoxic. Since hCG was a more potent stimulator of HIF1A than hypoxia itself in luteinising granulosa cells (van den Driesche et al. 2008), it is possible that the LH surge induces HIF1A expression directly. Thus, it is possible that any increases in VEGFA following the LH surge are mediated through the induction of HIF1A mRNA (Duncan et al. 2008). To date no studies have investigated HIF1A expression in ruminants during the follicular–luteal transition.
Periovulatory events: the breakdown of the basement membrane
The breakdown of the basement membrane involves a plethora of proteases that includes members of the matrix metalloprotease (MMP) family such as collagenases, gelatinases and membrane type (MT) MMP. Serine proteases such as plasmin, which is generated from plasminogen, are also involved by degrading fibrinogen and fibrin (Curry & Smith 2006). Several of these proteases are upregulated by the LH surge (e.g. MMP1, MMP9, MMP13, MT-MMP1 as well tissue and urokinase plasminogen activators), while others such as MMP2 are not (Bakke et al. 2002, 2004, Dow et al. 2002, Kliem et al. 2007, Berisha et al. 2008). These proteinases are nevertheless integral components in the ovulatory process. Furthermore, the administration of an anti-MMP2 antibody to sheep pre-ovulatory follicles not only disrupted ovulation but also the luteal tissue that was formed was vascular deficient (Gottsch et al. 2002). This suggests that protease activity and/or breakdown of the basement membrane is important for the initiation of luteal angiogenesis and is likely to have numerous effects: firstly, it removes the physical block to the vascularisation of the granulosa layer. Secondly, it could fragment and spread ECM components as well as creating a more spacious environment. This would generate conditions that are more conducive to endothelial (and other cells) motility and migration. Thirdly, any angiogenic factors sequestered in the basement membrane would be released. Finally, it could stimulate the differentiation of the follicular cells (e.g. granulosa cells exposed to fibronectin undergo luteinisation). The increased proteolytic activity would also stimulate the degradation of the ECM surrounding the existing vasculature, which is a pre-requisite for angiogenesis. This is supported by the observation that there is a decline in the vascular area in the periovulatory follicle (Cavender & Murdoch 1988, Martelli et al. 2006). However, the injection of galardin (a broad spectrum MMP inhibitor) to either normal or plasminogen-deficient mice had no effect on either ovulation rates or subsequent luteal vasculature (Wahlberg et al. 2007). Furthermore, there are no apparent reproductive defects in single MMP gene knockout mice (Wahlberg et al. 2007). These contrasting findings may reflect differences between species. Alternatively, there is considerable redundancy and overlapping of activities in the different proteases such that one protease can overcome the loss of another making it difficult to pinpoint the precise roles of each factor.
One protease that is critical for follicular development and ovulation in mice is a disintegrin and metalloproteinase with a TSP type 1 motif (ADAMTS1; Shozu et al. 2005). ADAMTS1 cleaves the matrix proteoglycans versican and aggrecan as well as pro-collagen, and is expressed in the periovulatory follicle. In addition, it is increased by gonadotrophin stimulation (Madan et al. 2003) and this may occur through the HIF1A pathway (Kim et al. 2009). ADAMTS1 might play a role in regulating endothelial cell invasion since it is transiently upregulated when these cells invade into collagen matrix following VEGFA/FGF2 stimulation. Moreover, small interfering RNA directed against ADAMTS1 attenuated the ability of endothelial cells to invade (Su et al. 2008). Conversely, the overproduction of ADAMTS1 enhanced infiltration of myofibroblasts and ECM deposition as well as accelerating tumour development (Su et al. 2008). Collectively, these studies suggest that ADAMTS1 might play a key role in the initial stages of angiogenesis following ovulation.
Perlecan is a large heparan sulphate proteoglycan (HSPG) that is a major constituent of both the follicular basal lamina and focimatrix that has been located between granulosa cells (Irving-Rodgers et al. 2006). It can sequester a number of angiogenic growth factors including FGF2. Heparanase is an endoglycosidase that cleaves polymeric heparan sulphate molecules from large HSPG. It was recently demonstrated that LH stimulated a rapid increase in heparanase mRNA and protein concentrations in the bovine granulosa cells (Klipper et al. 2009) and this could explain the disappearance of perlecan from collapsed follicles shortly after ovulation (Irving-Rodgers et al. 2006). This would then stimulate the release of sequestered factors such as FGF2 and heparan sulphates, thereby facilitating endothelial invasion. Moreover, FGF2 and VEGFA require not only their respective receptors but also co-receptors such as heparan sulphates and neuropilin respectively for their full biological activity (Ferrara et al. 2003, Presta et al. 2005). The potential modulatory role of these co-receptors is currently poorly characterised and warrants further investigation.
Cell migration, the role of fibroblasts and the ovulatory ‘wound’ hypothesis
Endothelial cell migration is a cyclical process involving its polarisation towards an angiogenic stimulus, protrusion through filopodia-like structures, traction and then retraction. Traction requires the protruding tip cell to adhere through integrins to the surface (e.g. ECM) over which it is moving. The integrins consist of and β chains that combine to form heterodimeric transmembrane receptors that act as ‘linker molecules’ between the ECM and the cytoskeleton of endothelial cells. Meanwhile, the production and organisation of ECM components such as fibronectin create a scaffold on to which endothelial cells can migrate (Hughes 2008). In the developing bovine CL, fibronectin forms a delicate network of fibrils that are orientated along the main axis of the capillary sprout (Amselgruber et al. 1999, Silvester & Luck 1999) thereby acting as a ‘pre-patterned’ guide line for endothelial cell migration. Fibronectin also has a profound stimulatory effect on luteal-derived endothelial cell proliferation (Christenson & Stouffer 1996) and formation of endothelial cell networks in vitro (Robinson et al. 2008). Similarly, during wound healing, fibroblasts are activated to myofibroblasts under stimulation from transforming growth factor β and FGF2 (Hughes 2008). These myofibroblasts then play an integral role by secreting and organising the components of the ECM (e.g. collagen I, IV and fibronectin). Pericytes have a similar phenotype to myofibroblasts and can also deposit ECM (see below for more details). It has traditionally been believed that the luteal steroidogenic cells stimulate endothelial cell migration towards themselves by producing chemo-attractants. Indeed, in the collapsed follicle, FGF2 and VEGFA, are primarily localised to these steroidogenic luteal cells in several species (Berisha et al. 2000b, Wulff et al. 2000, Kaczmarek, et al. 2007, Robinson et al. 2007). This then creates directionality for endothelial cell migration. However, FGF2 and VEGFA have also been localised to perivascular cells albeit to a lesser extent, suggesting that this process is far more complex than simple migration towards steroidogenic cells. It could be that different isoforms of VEGFA and/or FGF2 (e.g. those that are cell associated) are expressed in these perivascular cells. Alternatively, there could be other migratory stimuli. It is possible that the blood clot formed during ovulation might play an active role by creating a stimulus for migration. Indeed, platelets were more potent stimulants of endothelial cell migration than granulosa cells (Furukawa et al. 2007). However, the blood clot forms near to the ovarian surface and is relatively quickly removed (Duggavathi et al. 2003), although it could still create an environment whereby migration is supported. Intriguingly, we have observed that the endothelial cell clusters appear to migrate towards each other rather than to steroidogenic cells in our luteal angiogenic culture system that incorporates all cell types, (RS Robinson, KJ Woad, AJ Hammond, MG Hunter & GE Mann 2009, unpublished observations). This would indicate that it is the endothelial cells themselves (and not the steroidogenic cells) that produce the chemotactic factors, which then drive their migration and proliferation.
Endothelial proliferation and formation of vascular networks
The majority of the proliferating cells in the collapsed follicle are of vascular origin (Reynolds & Redmer 1999, Fraser & Lunn 2001). Both FGF2 and VEGFA are potent mitogens of endothelial cells and FGF2 and VEGFA stimulate bovine endothelial network formation in vitro (Robinson et al. 2008). Undoubtedly, VEGFA plays a fundamental role, since its blockade completely abolished endothelial proliferation, luteal vascularisation and progesterone production in the rat (Ferrara et al. 1998), primate (Wulff et al. 2001, Zimmermann et al. 2001, Hazzard et al. 2002) and mouse (Kuhnert et al. 2008). Recent studies in the cow have shown that local immunoneutralisation of VEGFA reduced luteal development and progesterone production (Yamashita et al. 2008) and the inhibition of VEGFA signalling suppressed the formation of endothelial networks in vitro (Woad et al. 2009). However, total inhibition was not achieved in both cases and whether this represents a species difference is unknown. Interestingly, treatment with the FGF receptor signalling inhibitor, SU5402, almost completely blocked endothelial network formation, by decreasing both the number of endothelial clusters and their size. This occurred even in the presence of exogenous VEGFA and indicates that FGF2 is critical for the formation of luteal endothelial networks. It also suggests that these factors must have complementary rather than redundant actions, since the remaining factors were unable to compensate for the loss of VEGF/FGF signalling (Woad et al. 2009). Combined with the dynamism of FGF2 during the follicular–luteal transition (Robinson et al. 2007), this emphasises the importance of FGF2 in controlling and possibly initiating luteal angiogenesis in the cow.
Pericytes and PDGF system
In a functional, mature vascular system, endothelial cells are supported by mural cells such as pericytes and vSMC. These mural cells provide structural support and regulate blood flow through their contractile properties. Pericytes share a basement membrane with the endothelial cells, but can make direct contact through peg-and-socket junctions. The final step in angiogenesis is vessel stabilisation, which occurs by the secretion of PDGFBB by endothelial cells, which acts in a paracrine manner to recruit pericytes (Gerhardt & Betsholtz 2003). Thus, for many years, pericytes were thought to have a passive role in angiogenesis and have been often neglected. There is now growing evidence that pericytes might play a more active role in initiating angiogenesis. This is not surprising since one of the first steps in angiogenesis is the detachment of pericytes from a sprouting vessel and once detached, pericytes can differentiate into collagen producing fibroblast-like cells (Gerhardt & Betsholtz 2003). Interestingly, during the ovulatory period, pericytes are located at what appears to be the forefront of the endothelial migratory path (Amselgruber et al. 1999, Redmer et al. 2001; Fig. 2A), whilst in the mature CL, they are closely associated with the endothelial cells (Fig. 2B). Furthermore, pericytes represent a large proportion of the proliferating cells in the early ovine CL (Redmer et al. 2001) and analysis of smooth muscle actin (a pericyte marker) staining during luteal development showed a biphasic pattern (Fig. 2C). It is possible that this represents two phases of pericyte activity: firstly that pericytes act as guiding structures aiding the outgrowth of endothelial cells. This is supported by the fact that pericytes produce MMPs and might promote endothelial cell invasion by degrading ECM. Indeed, synthetic MMP inhibitors blocked the ability of vSMC to invade extracellular matrices but did not affect their motility (Chantrain et al. 2006). The second phase is when pericytes are recruited during vessel stablisation. Collectively, these studies increase the evidence that pericytes playing a crucial and dynamic role during luteal angiogenesis.
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Comparative luteal angiogenesis |
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Blood flow and luteal function |
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Conclusion |
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Declaration of interest |
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Funding |
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Acknowledgements |
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Received July 7, 2009
First decision August 17, 2009
Revised manuscript received September 18, 2009
Accepted September 28, 2009
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Abstract
Introduction
