VASOACTIVE FACTORS IN ART CYCLES AND OVARIAN HYPERSTIMULATION SYNDROME

卵巢过度刺激综合征(OHSS)是妇女发病(严重时甚至死亡)的重要原因，尤其是在辅助生殖技术-胚胎移植(ART-ET)周期中药物促进多卵泡发育之后。虽然OHSS的发病机制尚不清楚，但它被认为是由于卵巢中血管活性物质的过度产生而引起的，而卵巢中的血管活性物质对排卵和黄体新生血管至关重要。该课题组最近提供的证据表明，新发现的作用于血管内皮细胞的旁分泌因子，即血管内皮生长/血管通透性因子(VEGF/VPF)和血管生成素(Ang)与排卵事件和OHSS有关。因此，建议进行研究以确定：(A)呈现这些血管活性物质作用的合成的药物方法是否会在不影响正常妊娠的情况下抑制卵巢活动。实验将在非人灵长类动物模型恒河猴和女性身上进行，以：(1)描述卵巢血管活性因子在自然月经周期与人工ART-ET周期中的动态变化，以及(2)检测与OHSS相关和不与OHSS相关的人工ART-ET周期中卵巢血管活性物质的表达；(3)测试抗血管活性物质在体内抑制卵巢活性的能力，而不阻止正常胚胎的妊娠启动。用半定量逆转录聚合酶链式反应分析排卵周卵泡和黄体细胞中VEGF-A、-B、C、D和Ang-1、-2的表达。蛋白质异构体的血管内皮生长因子-1和其他血管活性因子的产生将通过Western blotting和ELISA法测定。一种通用的抗血管化合物，即体内排卵周围卵泡/发育中的黄体，以及作用的特异性。ORPRC和OHSU的科学家们的这项合作项目将为内皮特异性血管活性物质在灵长类卵巢周期活动中的作用提供新的见解，可能识别可靠地预示OHSS排卵后发育的卵泡标志物，并提出预防或改善不孕妇女ART周期中OHSS的新疗法。

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.