ANGIOGENIC & ANGIOLYTIC FACTORS IN NATURAL & CONTROLLED OVARIAN STIMULATION CYCLE

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Aside from pathologic or trauma conditions, blood vessel development and degeneration in adults is essentially limited to the ovary and female reproductive tract, i.e., tissues that undergo cyclic growth and regression during the menstrual cycle. The long-range goal of this research is to understand the role of angiogenic and angiolytic factors in controlling vessel development, function and degeneration, and hence the structure-function of the ovulatory follicle and corpus luteum in primates. Progress was made in establishing (1) the presence and regulation of various components of the vascular endothelial growth factor (VEGF-A) system, and (2) the essential role for VEGF-A in follicle rupture (ovulation), as well as development of the functional corpus luteum, in the primate ovary. However, recent discoveries suggest that control of vascular events in the ovarian cycle involves additional local factors. Therefore, studies are proposed in a nonhuman primate, the rhesus monkey, and in women to test the hypotheses that: (a) the relative expression of angiopoietin agonists (Ang-1 and -4) and antagonists (Ang-2) influences maturity and function of VEGFinduced vessels, (b) the recently discovered "tissue-specific" factor, termed endocrine gland (EG)-VEGF complements the actions of VEGF-A to control the structure-function of the follicle and corpus luteum, and (c) excessive or aberrant production/action of Ang, EG-VEGF and/or VEGF-A is associated with controlled ovarian stimulation (COS) cycles, and is an etiologic factor in ovarian hyperstimulation syndrome (OHSS). Expression of mRNAs for ligands and receptors will be examined by real-time PCR and in situ hybridization. Protein production or secretion will be analyzed by Western blotting, ELISA assays and immunocytochemistry. Angiogenic (e.g., EG-VEGF) and angiolytic (e.g., Ang-2) substances will be injected directly into the preovulatory follicle and effects on vessel structure-function (e.g., permeability), ovulation, and the developing corpus luteum assessed. Continuing studies will evaluate whether alterations in circulating levels or ratios of angiogenic:angiolytic factors or their free:bound forms are associated with ovarian dysfunction, such as polycystic ovarian syndrome (PCOS) or OHSS, during infertility protocols in women. This collaborative effort between basic scientists at ONPRC and clinical researchers at OHSU should continue to provide new insight into the role of endothelial-specific angiogenic and angiolytic factors in normal ovarian cyclicity, and suggest novel therapies for preventing or ameliorating vascular defects in ovarian disorders.