VASOACTIVE FACTORS IN ART CYCLES AND OVARIAN HYPERSTIMULATION SYNDROME

卵巢过度刺激综合征（OHSS）是女性发病（严重时死亡）的重要原因，特别是在辅助生殖技术-胚胎移植（ART-ET）周期中药物促进多个卵泡发育后。虽然OHSS的发病机制尚不清楚，但据推测是由于卵巢中血管活性物质的过度产生和改变引起的，这些物质对排卵和黄体的新血管形成至关重要。该研究小组最近提供的证据表明，新发现的旁分泌因子专门作用于血管内皮细胞，即，血管内皮生长/血管通透性因子（VEGF/VPF）和血管生成素（ANG）与排卵期事件和OHSS相关。因此，建议进行研究以确定：（a）呈现这些血管活性物质的合成作用的药理学方法是否会抑制卵巢活性而不影响正常妊娠的可能性。将在非人灵长类动物模型（恒河猴）和女性中进行实验，以：（No.1）描述自然月经周期与人工ART-ET周期中卵巢血管活性因子的动态变化，与OHSS相关或不相关;（No.2）检查自然周期与ART周期中排卵期卵泡/黄体细胞区室中血管活性物质的表达;和（3）测试抗血管活性剂在体内抑制卵巢活性而不阻止正常胚胎发生的妊娠启动的能力。将通过半定量逆转录聚合酶链反应分析排卵期卵泡和黄体细胞中VEGF-A、-B、C和D以及ANG-1和-2的mRNA表达。VEGF-1和其他血管活性因子的蛋白质同种型的产生将通过蛋白质印迹和ELISA来确定。一种通用的血管抑制化合物，在体内对排卵期卵泡/发育中的黄体具有抑制作用，以及特异性作用。ORPRC和OHSU科学家之间的这个合作项目应该为内皮特异性血管活性药物在灵长类动物卵巢周期活动中的作用提供新的见解，可以确定可靠预示排卵后OHSS发展的卵泡标志物，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.