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The critical importance of ovarian angiogenesis.

The vascular system develops through two distinct pathways known as vasculogenesis and angiogenesis. The former involves formation of vascular networks from endothelial progenitor cells (Kasmeyer et al. 2009), while angiogenesis is the extension of new blood vessels from pre-existing ones (Robinson et al. 2009). The establishment and optimal functioning of the vasculature is an essential component throughout the body and the ovary is no exception. Blood vessel growth is tightly regulated requiring the timely balance between proand antiangiogenic growth factors as well as the complex, intimate interplay between endothelial cells and various other cell types (e.g. immune cells and pericytes). In this Research Front on ovarian angiogenesis, we present four reviews and one original article that reveal the latest research and current hypotheses on the key stages of vascular development in the ovary. Remarkably little was known about how the vasculature in the fetal ovary is formed, until recently. In the first paper of this Research Front, the latest insights are highlighted byMcFee and Cupp (2012). Intriguingly, ovarian vasculature in the embryo appears to develop through a vasculogenic process rather than the typical angiogenesis that occurs in embryonic testes. Moreover, the vascular patterning is preferentially aligned along the neuronal network template and thus could be influenced by neuronal growth factors (Anderson et al. 2002). McFee and Cupp (2012) also suggest that the ability of germ cell/oocytes to proliferate, develop and form primordial follicles is potentially influenced by fetal ovarian medulla blood supply since these cells lack a direct blood supply. Indeed, follicle assembly initially originates near to the medullary vasculature (Sawyer et al. 2002). This would imply that the inappropriate development of an ovarian vasculature could result in improper prenatal folliculogenesis. This could then adversely affect fertility of both women and animals. The VEGF system is very complex with the existence of numerous proand anti-angiogenic isoforms, receptors and signalling partners (Gabhann and Popel 2008).McFee and Cupp (2012) provide a scholarly account of their importance in the regulation of fetal ovarian development. They speculate that the temporal differences in expression of pro-angiogenic ‘a’ and anti-angiogenic ‘b’ VEGFA isoforms might explain the different patterns of vascularisation in the fetal ovary and testes (McFee andCupp 2012). Interestingly, Qiu et al. (2012) recently showed that overexpression of VEGF165b reduced follicular development and number of ovulations and more importantly, this was associatedwith lower fertility inmice. Collectively, this further emphasises that optimal ovarian function requires an appropriate balance between proand anti-angiogenic factors. It is well established that hypoxia-induced expression of VEGFA plays a pivotal role in stimulating angiogenesis during tumour development. However, the exact role of hypoxia in ovarian angiogenesis has remained elusive for a long time. In the second review of this Research Front, Meidan et al. (2012) discuss the role of the transcription factor, hypoxia inducible factor 1p/b (HIF1p/b), which is critical for ovulation in mice (Kim et al. 2009). The current evidence indicates that HIF1pis upregulated and translocates to the nucleus of luteinising granulosa cell during the ovulatory window although this upregulation is only short-lived. It is likely that, at least in part, the LH surge upregulates the HIF1p in luteinising follicular cells (van den Driesche et al. 2008). This feature of HIF1p regulation could be unique to the ovary. It is also increasingly apparent that any induction of HIF1pstimulates VEGFA expression in luteal cells (Zhang et al. 2011). What is less well known is the role of hypoxia and/or HIF1pin the regulation of FGF2. This certainly requires investigation since FGF2 and HIF1p expression profiles are closelymatched in the bovine CL (Robinson et al. 2007; Nishimura and Okuda 2010). Furthermore, it is becoming increasing apparent that FGF2 is a key factor controlling endothelial cell sprouting during the follicle-luteal transition in cattle (Laird et al. 2012). Accurate measurement of tissue hypoxia is challenging and will continue to hinder the elucidation of the role hypoxia plays in ovarian angiogenesis. The use of novel, live imaging positron emission tomography (PET) technologies using biomarkers such as F-labelled fluoromisonidazole (F-MISO) as used in tumour biology (Mendichovszky and Jackson 2011) will help to address this challenge. Furthermore, such technologiesmight increase our understanding of the role of hypoxia in disorders such as luteal deficiency. It has been long-recognised that ovulation has numerous characteristics of an inflammatory response. However, the role of immune cells in the regulation of ovarian angiogenesis has been neglected, until recently and these findings are highlighted by Shirasuna et al. (2012) in the third review. While there are some definite species differences, there is a pool of evidence that immune cells (e.g. neutrophils, macrophages and/or lymphocytes) infiltrate into the developing CL. This is likely due to CSIRO PUBLISHING