ANGIOGENIC & ANGIOLYTIC FACTORS IN NATURAL & CONTROLLED OVARIAN STIMULATION CYCLE

除了病理或创伤情况外，成人的血管发育和退化基本上是 仅限于卵巢和女性生殖道，即经历周期性生长和退化的组织 在月经周期中。这项研究的长期目标是了解血管生成的作用 和血管溶解因子控制血管的发育、功能和退化，因此 灵长类动物排卵卵泡和黄体的结构与功能。在建立基础设施方面取得进展 (1)血管内皮细胞生长因子(VEGF-A)各成分的存在及其调控 以及(2)血管内皮生长因子-A在卵泡破裂(排卵)以及卵泡发育中的重要作用。 灵长类卵巢中的功能性黄体。然而，最近的发现表明，血管的控制 卵巢周期中的事件涉及到额外的局部因素。因此，在非人类中提出了研究 在灵长类动物、恒河猴和女性身上测试假说：(A)相对表达 血管生成素激动剂(Ang-1和-4)和拮抗剂(Ang-2)影响血管内皮生长因子诱导的成熟度和功能 血管，(B)最近发现的“组织特异性”因子，称为内分泌腺(EG)-血管内皮生长因子 补充血管内皮生长因子-A控制卵泡和黄体结构功能的作用，以及 (C)血管紧张素转换酶、EG-血管内皮生长因子和/或血管内皮生长因子-A的过度或异常产生/作用与受控有关 卵巢刺激(COS)周期，是卵巢过度刺激综合征(OHSS)的病因之一。 配体和受体的mRNAs的表达将通过实时荧光聚合酶链式反应和原位杂交进行检测。 蛋白质的产生或分泌将通过蛋白质印迹、ELISA法和免疫细胞化学进行分析。 血管生成物质(例如EG-VEGF)和血管溶解物质(例如Ang-2)将直接注射到 排卵前卵泡及其对血管结构-功能(如通透性)、排卵和排卵的影响 评估黄体发育情况。持续的研究将评估循环水平的变化 或血管生成与血管溶解因子的比率或其游离结合形式与卵巢功能障碍有关， 如多囊卵巢综合征(PCOS)或OHSS。这 ONPRC的基础科学家和OHSU的临床研究人员之间的合作努力应该继续 为内皮特异性血管生成和血管溶解因子在正常卵巢中的作用提供新的见解 周期性，并建议新的治疗方法来预防或改善卵巢疾病的血管缺陷。

Aside from pathologic or trauma conditions, blood vessel development and degeneration in adults is essentially limited to the ovary and female reproductive tract, i.e., tissues that undergo cyclic growth and regression during the menstrual cycle. The long-range goal of this research is to understand the role of angiogenic and angiolytic factors in controlling vessel development, function and degeneration, and hence the structure-function of the ovulatory follicle and corpus luteum in primates. Progress was made in establishing (1) the presence and regulation of various components of the vascular endothelial growth factor (VEGF-A) system, and (2) the essential role for VEGF-A in follicle rupture (ovulation), as well as development of the functional corpus luteum, in the primate ovary. However, recent discoveries suggest that control of vascular events in the ovarian cycle involves additional local factors. Therefore, studies are proposed in a nonhuman primate, the rhesus monkey, and in women to test the hypotheses that: (a) the relative expression of angiopoietin agonists (Ang-1 and -4) and antagonists (Ang-2) influences maturity and function of VEGFinduced vessels, (b) the recently discovered "tissue-specific" factor, termed endocrine gland (EG)-VEGF complements the actions of VEGF-A to control the structure-function of the follicle and corpus luteum, and (c) excessive or aberrant production/action of Ang, EG-VEGF and/or VEGF-A is associated with controlled ovarian stimulation (COS) cycles, and is an etiologic factor in ovarian hyperstimulation syndrome (OHSS). Expression of mRNAs for ligands and receptors will be examined by real-time PCR and in situ hybridization. Protein production or secretion will be analyzed by Western blotting, ELISA assays and immunocytochemistry. Angiogenic (e.g., EG-VEGF) and angiolytic (e.g., Ang-2) substances will be injected directly into the preovulatory follicle and effects on vessel structure-function (e.g., permeability), ovulation, and the developing corpus luteum assessed. Continuing studies will evaluate whether alterations in circulating levels or ratios of angiogenic:angiolytic factors or their free:bound forms are associated with ovarian dysfunction, such as polycystic ovarian syndrome (PCOS) or OHSS, during infertility protocols in women. This collaborative effort between basic scientists at ONPRC and clinical researchers at OHSU should continue to provide new insight into the role of endothelial-specific angiogenic and angiolytic factors in normal ovarian cyclicity, and suggest novel therapies for preventing or ameliorating vascular defects in ovarian disorders.