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

描述（由申请方提供）：拟在恒河猴（一种极好的女性生殖健康非人灵长类动物模型）中进行研究，以检查关键局部因子血管内皮生长因子（VEGF）在控制排卵周期（COS）期间对绒毛膜促性腺激素（CG）反应中的作用。本R21申请中提出的实验应区分CG的VEGF依赖性和独立性作用，从而导致卵巢过度刺激综合征（OHSS）的早期和晚期发作症状。尚未在灵长类动物中直接研究CG诱导的VEGF诱导与OHSS发作相关的显著卵巢/全身通透性过高的作用。患有多囊卵巢综合征的女性（PCOS约占美国女性的5-10%）在COS治疗不孕症期间发生OHSS的风险很高-在COS期间避免OHSS是不孕症专家的主要关注点。迄今为止，对生殖组织的血管结构/功能与局部血管生成因子的作用之间的关系的研究一直是间接的或静态的，涉及组织切除后的单一观察。PI应用了敏感的微创技术，能够重复测量非人灵长类动物卵巢和子宫中的血管结构-功能。对比增强超声（CE-US）和动态对比增强磁共振成像（DCE-MRI）方案允许直接量化生殖组织的血流/体积和组织渗透性。值得注意的是，它是可能的，同时应用所提出的新的成像方法的子宫，以及卵巢，辨别血管内皮生长因子依赖与独立的影响CG血管动力学在灵长类动物。除了量化VEGF中和对生殖组织血管功能的影响外，还将量化对其他血管生成因子（血管生成素，ANGPT）的影响，作为OHSS的可能治疗干预措施。这些实验的结果将指导未来的研究，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。这些技术可用于识别和评估针对有OHSS和不孕风险的女性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.