Effects of CG and VEGF on the vasculature of the primate ovary and uterus

描述(申请人提供)：本研究旨在研究恒河猴在控制排卵周期(COS)中对绒毛膜促性腺激素(CG)反应的关键局部因子血管内皮生长因子(VEGF)的作用，恒河猴是研究女性生殖健康的优秀非人类灵长类动物模型。在R21应用中提出的实验应该区分CG的血管内皮生长因子依赖和独立作用，从而导致卵巢过度刺激综合征(OHSS)的早发和晚发症状。在灵长类动物中，CG诱导的血管内皮生长因子在诱导卵巢/全身性高通透性与OHSS的发病相关方面的作用尚未被直接研究。患有多囊卵巢综合征(PCOS~约占美国女性的5%-10%)的妇女在COS期间因不孕治疗而发生OHSS的风险很高。在COS期间避免OHSS是不孕不育专家的主要担忧。到目前为止，对生殖组织血管结构/功能与局部血管生成因子作用关系的研究大多是间接的或静态的，只涉及组织切除后的单次观察。PI应用了敏感的微创技术，可以重复测量非人类灵长类动物卵巢和子宫的血管结构和功能。对比增强超声(CE-US)和动态对比增强磁共振成像(DCE-MRI)协议允许直接量化生殖组织的血流量/体积和组织通透性。值得注意的是，可以同时将所提出的新的成像方法应用于子宫和卵巢，以辨别CG对灵长类动物血管动力学的依赖和非依赖的影响。除了量化VEGF中和对生殖组织血管功能的影响外，对其他血管生成因子(血管生成素，ANGPTs)的影响也将被量化为OHSS的可能治疗干预措施。这些实验的结果将指导未来通过成像和分子方法研究影响卵巢和子宫/全身血管功能的新分子。这些技术可用于确定和评估针对有OHSS和不孕症风险的妇女的特定治疗干预措施。

DESCRIPTION (provided by applicant): Studies are proposed to examine the role of a critical local factor, vascular endothelial growth factor (VEGF) in the response to chorionic gonadotropin (CG) during controlled ovulation cycles (COS) in rhesus macaques, an excellent non-human primate model of women's reproductive health. The experiments proposed in this R21 application should discern between the VEGF-dependent and independent actions of CG resulting in early and late onset symptoms of ovarian hyperstimulation syndrome (OHSS). The contribution of CG-induced VEGF to induce the marked ovarian/systemic hyperpermeability associated with onset of OHSS has not been directly investigated in primates. Women with polycystic ovarian syndrome (PCOS~ approximately 5-10% of women in the USA) are at high risk for developing OHSS during COS for infertility treatments~ avoidance of OHSS during COS is a major concern for infertility specialists. To date, investigations into the relationship betwen vascular structure/function of reproductive tissues and actions of local angiogenic factors have been indirect or static in nature involving single observations after tissue removal. The PI has applied sensitive, minimally invasive techniques enabling repeated measurements of vascular structure-function in the ovaries and uterus of nonhuman primates. Contrast enhanced-Ultrasound (CE-US) and Dynamic Contrast Enhanced- Magnetic Resonance Imaging (DCE-MRI) protocols allow direct quantification of blood flow/volume and tissue permeability of reproductive tissues. Notably, it is possible to simultaneously apply the proposed novel imaging approaches to the uterus, as well as the ovary, to discern the VEGF-dependent versus-independent effects of CG on vascular dynamics in primates. In addition to quantifying the effects of VEGF neutralization on vascular function of reproductive tissues, effects on other angiogenic factors (angiopoietins, ANGPTs) will be quantified as possible therapeutic interventions for OHSS. The results of these experiments will guide future studies investigating novel molecules affecting both ovarian and uterine/systemic vascular function by both imaging and molecular methods. These techniques can be used to identify and evaluate specific therapeutic interventions for women at risk for OHSS and infertility.