Ovarian hyperstimulation syndrome (OHSS) is a significant cause of morbidity (and in severe case, mortality) in women, particularly following pharmacologic promotion of multiple follicular development in assisted reproductive technology-embryo transfer (ART-ET) cycles. Although the pathogenesis of OHSS is unknown, it is hypothesized to arise from the over-production of alteration of vasoactive substances in the ovary that in the ovary that are critical for ovulation and neovascularization of the corpus luteum. This research group recently provided evidence that newly-discovered paracrine factors acting specifically on vascular endothelial cells, i.e., vascular endothelial growth/vascular permeability factors (VEGF/VPF) and angiopoietins (ANG) are associated with periovulatory events and OHSS. Therefore, studies are proposed to determine if: (a) pharmacologic approaches that present the synthesis of action of these vasoactive substances will suppress ovarian activity without compromising the potential for normal pregnancy. Experiments will be performed in a non-human primate model, the rhesus monkey, and in women, to: (No. 1) delineate the dynamics of ovarian vasoactive factors in natural menstrual cycles versus artificial ART-ET cycles associated with and without OHSS; (No. 2) examine the expression of vasoactive substances in cellular compartments of the periovulatory follicle/corpus luteum in natural versus ART cycles; and (No. 3) test the ability of anti-vasoactive agents to suppress ovarian activity in vivo without preventing pregnancy initiation of normal embryogenesis. Expression of mRNAs for VEGF-A, -B, C and D plus ANG-1 and -2 in cells of the periovulatory follicles and corpus luteum will be analyzed by semi-quantitative reverse transcription polymerase chain reaction. Production of protein isoforms of VEGF-1 and other vasoactive factors will be determined by Western blotting and ELISA. A general angiostatic compound the periovulatory follicle/developing corpus luteum in vivo, as well as specificity of action. This collaborative project between scientists at ORPRC and OHSU should provide new insight into the role of endothelial-specific vasoactive agents in the cyclic activity of the primate ovary, may identify follicular markers that reliably portend post-ovulatory development of OHSS, plus suggest novel therapies for preventing or ameliorating OHSS during ART cycles in infertile women.
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