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Receptor/Ligand Signals for Ovarian Follicular Angiogenesis

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Ovarian vasculature increases during development of normal follicles as well as ovarian cancer/tumors, but molecular mechanisms that initiate ovarian angiogenesis are not well defined. Based on high-density microarray analysis comparing granulosa cell gene expression in cystic and noncystic follicles, we discovered that granulosa cell angiogenin (ANG) mRNA is up-regulated and fibroblast growth factor-9 (FGF9) mRNA is down-regulated in cystic follicles suggesting that angiogenic factors are involved in cyst formation. Our overall hypothesis is that granulosa cells signal theca interna via ANG and FGF9 secretion to regulate theca and vascular cell differentiation and proliferation during follicular development. As the follicle grows, theca and granulosa cells must proliferate with minimal differentiation while thecal vascularization increases so that follicles do not prematurely ovulate or luteinize before the oocyte is fully mature. Thus, aberrant production of ANG and/or FGF9 may lead to vascular dysfunction and ovarian disorders. In preliminary studies using experimental paradigms developed in our bovine granulosa and theca cell model, we demonstrated that: 1) abundance of ANG and FGF9 mRNA in bovine granulosa cells of cystic and normal follicles differ;2) abundance of ANG mRNA is increased by insulin-like growth factor-I (IGF1) in granulosa cells;and 3) FGF9 stimulates theca cell mitosis while inhibiting theca cell differentiation. In Specific Aim 1, we will investigate the developmental regulation of ANG and FGF9 mRNA in granulosa cells and FGF9 receptors in theca cells during follicular development in vivo using real-time quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) as well as measure ANG and FGF9 in follicular fluid via ELISA. Specific Aim 2 will determine the hormonal regulation of ANG and FGF9 production by granulosa cells using qRT-PCR (mRNA) and ELISA (protein). In Specific Aim 3, we will determine if changes in cell-cycle proteins and steroidogenic enzymes are associated with FGF9-altered theca cell proliferation and steroidogenesis, and identify additional genes regulated by FGF9 using microarray technology. These studies will provide insight into the physiological control of ANG and FGF9 production and determine mechanisms by which ANG and FGF9 regulate theca cell functions. Our studies have lead to newly discovered markers for cystic follicles and may also lead to new options for improved treatment of female infertility and ovarian pathologies such as polycystic ovarian disease and ovarian cancer. The proposed research will provide valuable research training experiences for students and expose many more students to the excitement of scientific discovery.

PUBLIC HEALTH RELEVANCE: Increased vascularity occurs during normal ovarian follicle development, and studies show that blood vessel growth (angiogenesis) is activated in ovarian carcinomas. Our findings of increased expression of angiogenin in cystic follicles may indicate that an increased vascularity is part of the mechanism of development of cystic follicles. Along with providing advances in our understanding of female fertility and valuable research training experiences for undergraduate students, these studies should lead to new options for improved treatment of female infertility and ovarian pathologies such as polycystic ovarian disease and ovarian cancer.

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