Recent advances were made in understanding the processes that regulate the development, maintenance and remodeling of the vasculature in tissues. These concepts are relevant to the control of reproduction since normal angiogenesis in adults is almost exclusively limited to cyclic changes in the ovary and reproductive tract. Notably, the periovulatory events of follicle rupture and conversion of the follicle into the corpus luteum involve remarkable changes in vascular permeability and neovascularization of the granulosa layer destined to form luteal tissue. Thus, agents that disrupt these vascular processes could suppress the gamete (oocyte) or hormonal (i.e., progesterone) components necessary for fertility and intrauterine implantation. To test this hypothesis, experiments were initiated in a nonhuman primate model, the rhesus monkey, to (Aim No. 1) determine if two categories of anti-angiogenic agents, a general angiostatic compound (AGM-1470) and a specific anti -vascular endothelial growth factor (anti-VEGF), block ovulation or impair the development/function of the corpus luteum of the menstrual cycle. Either vehicle or drug will be injected directly into the preovulatory follicle (day 0 to 1 post-gonadotropin surge). In phase one, laparoscopic evaluation and analyses of steroid levels in daily serum samples will evaluate follicle rupture and the function/lifespan of the corpus luteum. In phase two, hemiovariectomy 4 days after injection will provide tissues for morphometric, immunocytochemical and molecular analyses of the developing corpus luteum, including its vasculature. Experiments are also planned (Aim No. 2) to establish the specificity of action of anti-angiogenic agents in the primate ovary. Although these drugs are proposed to act specifically on vascular endothelial cells, it is important to determine if there are effects on other ovarian cell types. Finally, to determine if there are any extra-ovarian effects due to drug that reaches the reproductive tract, histologic and morphometric analyses of uterine biopsies will be performed. It is expected that a working dose for at least one anti-angiogenic agent may be defined for further preclinical trials evaluating its potential via systemic administration as a novel contraceptive acting to block ovulation and/or implantation. FUNDING World Health Organization (RF96020 #75), NIH HD22408 PUBLICATIONS None
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