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Angiogenesis and Vascular Function in the Ovary

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Angiogenesis and Vascular Function in the Ovary REPRODUCTIONREVIEW Focus on Vascular Function in Female Reproduction Angiogenesis and vascular function in the ovary R S Robinson1, K J Woad2, A J Hammond2, M Laird1, M G Hunter2 and G E Mann2 1School of Veterinary Medicine and Science and 2Division of Animal Sciences, University of Nottingham, Sutton Bonington Campus, Loughborough, Leicestershire, LE12 5RD, UK Correspondence should be addressed to R S Robinson; Email: [email protected] Abstract Ovarian function is dependent on the establishment and continual remodelling of a complex vascular system. This enables the follicle and/or corpus luteum (CL) to receive the required supply of nutrients, oxygen and hormonal support as well as facilitating the release of steroids. Moreover, the inhibition of angiogenesis results in the attenuation of follicular growth, disruption of ovulation and drastic effects on the development and function of the CL. It appears that the production and action of vascular endothelial growth factor A (VEGFA) is necessary at all these stages of development. However, the expression of fibroblast growth factor 2 (FGF2) in the cow is more dynamic than that of VEGFA with a dramatic upregulation during the follicular–luteal transition. This upregulation is then likely to initiate intense angiogenesis in the presence of high VEGFA levels. Recently, we have developed a novel ovarian physiological angiogenesis culture system in which highly organised and intricate endothelial cell networks are formed. This system will enable us to elucidate the complex inter-play between FGF2 and VEGFA as well as other angiogenic factors in the regulation of luteal angiogenesis. Furthermore, recent evidence indicates that pericytes might play an active role in driving angiogenesis and highlights the importance of pericyte–endothelial interactions in this process. Finally, the targeted promotion of angiogenesis may lead to the development of novel strategies to alleviate luteal inadequacy and infertility. Reproduction (2009) 138 869–881 Introduction proliferate under the influence of proangiogenic factors. Once connected and aligned, the endothelial cells Angiogenesis, the formation of new blood vessels from form a lumen and the newly formed vessel is then existing ones, involves a complex series of cellular stabilised by the recruitment of pericytes (Gerhardt & processes and molecular changes. In adults, it is largely Betsholtz 2003). Thus, angiogenesis is a highly regulated limited to pathological situations such as tumour growth process involving a balance between a plethora of and wound healing. However, the ovary undergoes pro- and anti-angiogenic factors. continual cyclical changes and so requires continual angiogenesis (Reynolds & Redmer 1999, Fraser & Lunn 2001). An established vasculature consists of an inner Key angiogenic regulators lining of endothelial cells, associated mural cells such as The principal proangiogenic factors include fibroblast pericytes and vascular smooth muscle cells (vSMC). growth factor 2 (FGF2), VEGFA, plaletet-derived growth These vessels remain quiescent until there is an factor (PDGF) family and the angiopoietin (ANGPT) angiogenic stimulus such as hypoxia or wounding, system. They have many overlapping functions but there which then upregulates proangiogenic factors, such as are some important differences. These factors and vascular endothelial growth factor A (VEGFA; Gerhardt associated properties are summarised in Table 1. & Betsholtz 2003). After this stimulus, the existing Blockade of VEGFA/PDGF signalling has highlighted vessels start to destabilise through the disruption of the critical roles that these factors play in controlling endothelial and mural cellular contacts. At the same not only angiogenesis but also ovarian function. For time, numerous proteases are activated and the extra- example, inhibition of VEGFA signalling by various cellular matrix (ECM) is degraded. Endothelial cells, methods disrupted ovulation, completely blocked the then, migrate towards the angiogenic stimuli and vascularisation of the subsequent corpus luteum (CL) and prevented the post-ovulatory rise in progesterone This paper is one of four papers that form part of a special Focus Issue (Fraser & Lunn 2001). Conversely, much less is section on Vascular Function in Female Reproduction. The Guest Editor generally known about the anti-angiogenic factors. for this section was H N Jabbour, Edinburgh, UK. They generally associate with the ECM and suppress q 2009 Society for Reproduction and Fertility DOI: 10.1530/REP-09-0283 ISSN 1470–1626 (paper) 1741–7899 (online) Online version via www.reproduction-online.org Downloaded from Bioscientifica.com at 09/28/2021 11:13:37PM via free access 870 R S Robinson and others Table 1 The principal angiogenic factors and their associated properties. Biochemical Receptor/cellular Ligand Isoforms properties target Functions References Pro-angiogenic growth factors VEGFA VEGFA121 Binds to heparin and ECM VEGFR1 (FLT) (signal- Stimulates endothelial Ferrara et al. (2003) VEGFA145 (except VEGFA121) ling capability is proliferation, VEGFA165 VEGFA121, 145 and 165 are unresolved) migration and tube VEGFA189 secreted and soluble while VEGFR2 (KDR) formation VEGFA206 VEGFA189, 206 are cell (tyrosine kinase Vascular permeability associated activity) factor FGF2 18 kDa Heparin binding FGFR1-4 (tyrosine Stimulates endothelial Presta et al. (2005) (cytoplasmic) kinase activity) proliferation and 22–34 kDa migration (nuclear) Mitogen for fibroblasts Cell differentiation PDGF PDGFA Dimerisation required for PDGFRA (PDGFAA, Activation of PDGFRB Fredriksson et al. PDGFB activity AB, BB) PDGFRB by PDGFBB stimu- (2004) PDGFC PDGFAA, BB (homodimers) (PDGFBB) lates recruitment of PDGFD PDGFAB (heterodimer) Both tyrosine kinase pericytes receptors ANGPT ANGPT1 Tie2 (tyrosine kinase ANGPT1 stimulates Maisonpierre et al. ANGPT2 receptor) vessel maturation (1997) ANGPT1 activates while ANGPT2 Tie2 destabilises endo- ANGPT2 is an thelial–pericyte endogenous contacts antagonist Anti-angiogenic factors Thrombospondin TSP1 and TSP2 High molecular weight CD36 TSP1: induces endo- Armstrong & Bornstein glycoprotein Integrin associated thelial apoptosis (2003) Heparin binding ECM protein (IAP, CD47) and destabilises associated endothelial cell contacts TSP2: inhibits endothelial cell migration Angiostatin – Produced by cleavage of avb3 integrin Inhibits endothelial Wahl et al. (2005) plasminogen by protease cell proliferation Contain kringle domains and migration angiogenesis by inhibiting endothelial migration or There is remarkably little information regarding stimulating apoptosis in endothelial cells (Armstrong & how the follicle initially recruits its vascular network. Bornstein 2003). The likely candidate is VEGFA, which is first detected in This review will focus on angiogenesis and its the granulosa and theca layers of secondary follicles regulation during the key stages of the follicular–luteal in cows (Yang & Fortune 2007) while ANGPT and timeline in farm animals, but also incorporates data from FGF2 do not appear in these cells until the antral other species where appropriate. This timeline includes stages (van Wezel et al. 1995, Hayashi et al. 2004). the recruitment of the theca layer, antral follicle Furthermore, administration of VEGFA stimulated the development and dominance, ovulation and subsequent development of secondary follicles in cows (Yan g & luteal development. Fortune 2007). While VEGF trap administration in primates reduced the endothelial cell area of secondary follicles and inhibited the formation of antral follicles Initial recruitment of thecal vasculature (Wulff et al. 2002). Both primordial and primary follicles receive sufficient However, it is unclear what stimulates VEGFA nutrients and oxygen by passive diffusion from stromal expression because hypoxia-induced factor 1a (HIF1A) blood vessels. However, the formation of an individual (a transcription factor induced by hypoxia and a potent capillary network around each follicle is required for inducer of VEGFA) was absent from pre-antral follicles follicles to grow beyond these stages. This network is (Duncan et al.2008). It is also unlikely to be initially thin, roughly structured and has a single layer. gonadotrophins because pre-antral follicle growth is It is confined to the theca layer with the granulosa gonadotrophin independent. It could alternatively be layer remaining avascular throughout folliculogenesis an oocyte-derived factor. Both PDGF and FGF2 are (Tamanini & De Ambrogi 2004). present in the oocyte of primordial and primary Reproduction (2009) 138 869–881 www.reproduction-online.org Downloaded from Bioscientifica.com at 09/28/2021 11:13:37PM via free access Ovarian angiogenesis 871 follicles (van Wezel et al. 1995, Nilsson et al. 2006). have begun to shed more light on this issue. In mares, the Additionally, both factors promote the primordial to follicles that became dominant had an increased blood primary transition, pre-antral follicular growth and flow prior to deviation when compared to their recruitment of theca cells (Nilsson et al. 2006, Matos subsequent subordinates (Acosta et al. 2004). While a et al. 2007). However, their effects on theca vascularity similar study in the cow was less conclusive, there are currently unknown. 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 Pre-antral follicular vasculature understanding of the regulation
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