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

CG和VEGF对灵长类卵巢和子宫脉管系统的影响

• 批准号: 8898173
• 负责人: CECILY V BISHOP
• 金额: $ 21.33万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-25 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8898173
• 关键词: Abdomen; Adult; Adverse event; Affect; Angiogenic Factor; Angiopoietin-1; Angiopoietin-2; Angiopoietins; Ascites; Avastin; Blood; Blood Vessels; Blood flow; Chorionic Gonadotropin; Diagnosis; Diagnostic; Disease; Doppler Ultrasound; Embryo; Endometrial; Endometrium; Excision; Experimental Designs; Exposure to; Female; Future; Growth; Health; Hormones; Image; Implant; Infertility; Investigation; Iron; Longevity; Luteal Phase; Luteinizing Hormone; Macaca; Macaca mulatta; Magnetic Resonance Imaging; Measurement; Measures; Menstrual cycle; Methods; Modeling; Molecular; Molecular Weight; Monitor; Nature; Ovarian; Ovarian Diseases; Ovarian Hyperstimulation Syndrome; Ovarian Stimulations; Ovary; Ovulation; Pathologic; Permeability; Physiological; Pregnancy; Primates; Prohance; Proteins; Protocols documentation; Reagent; Reproductive Health; Research; Risk; Role; Signal Transduction; Specialist; Staging; Stimulus; Structure; Symptoms; Syndrome; Techniques; Testing; Therapeutic Intervention; Tissues; Treatment Efficacy; Ultrasonography; Uterus; Vascular Endothelial Growth Factors; Vascular Permeabilities; Vascular remodeling; Woman; aged; base; bevacizumab; capillary bed; contrast enhanced; corpus luteum; early onset; high risk; implantation; insight; minimally invasive; molecular imaging; neovascularization; nonhuman primate; novel; reproductive; reproductive function; research study; response

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.

描述（由申请人提供）：拟进行研究以检验关键局部因子血管内皮生长因子 (VEGF) 在恒河猴受控排卵周期 (COS) 期间对绒毛膜促性腺激素 (CG) 的反应中的作用，恒河猴是一种极好的非促排卵周期。 -女性生殖健康的人类灵长类动物模型。该 R21 申请中提出的实验应区分 CG 的 VEGF 依赖性和独立作用，从而导致卵巢过度刺激综合征 (OHSS) 的早期和晚期症状。 CG 诱导的 VEGF 诱导与 OHSS 发病相关的显着卵巢/全身通透性过高的作用尚未在灵长类动物中进行直接研究。患有多囊卵巢综合症的女性（PCOS~大约占美国女性的 5-10%）在 COS 不孕治疗期间发生 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关系的研究本质上是间接或静态的，涉及组织去除后的单一观察。 PI 采用灵敏的微创技术，能够重复测量非人类灵长类动物卵巢和子宫的血管结构功能。对比增强超声 (CE-US) 和动态对比增强磁共振成像 (DCE-MRI) 协议可以直接量化生殖组织的血流量/体积和组织渗透性。值得注意的是，可以同时将所提出的新型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 VEGF 依赖性和独立性影响。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的研究。这些技术可用于识别和评估针对有 OHSS 和不孕症风险的女性的具体治疗干预措施。