The Role of Leptin in the Vascularization of the Developing Corpus Luteum

描述（由申请人提供）：黄体（CL）是哺乳动物物种中负责维持妊娠的卵巢结构，通过产生类固醇激素孕酮。黄体缺陷导致生殖异常，约占生殖失败的65%。黄体发育异常导致孕酮产生减少，随后不能支持发育中的胎儿。异常/发育不全的CL在很大程度上归因于异常血管生成。已知有许多因子调节黄体血管生成，包括血管内皮生长因子（VEGF）和成纤维细胞生长因子2（FGF-2）。所有这些因子都在卵巢组织中产生，对应于高血管生成活性时期（排卵卵泡和CL发育），并受促黄体激素LH（促黄体生成激素）调节。感兴趣的是LH刺激卵巢卵泡产生瘦素的能力，瘦素是一种主要在脂肪组织中产生的有效饱腹激素。瘦素是一种重要的代谢激素，具有生殖和血管生成功能。此外，瘦素影响非卵巢组织中VEGF和FGF-2的功能。此外，已在发育中的黄体组织中鉴定出瘦素受体（OB-Rb）的全功能形式，这意味着瘦素参与黄体功能。此外，本文报道的初步数据显示，瘦素在发育中的CL组织中上调FGF-2和VEGF。这一发现是新颖的，因为许多研究认为瘦素在卵巢中的作用是类固醇生成过程中的调节剂。然而，瘦素的调节能力充其量是中等的。除了瘦素对血管生成因子的调节外，初步数据显示，瘦素生物活性的丧失增加了异常黄体形成的频率。因此，LH调节瘦素的能力，瘦素调节黄体组织中血管生成因子的能力，以及由于生物可利用瘦素减少而导致的异常CL的发生，表明瘦素可能在CL的发展中起重要作用。因此，据推测，瘦素是重要的血管生成过程中发展CL。所提出的实验旨在检验这一假设，并开始了解瘦素调节发育中黄体组织血管生成的机制。本文提出的研究的具体目的是1）确定瘦素与体内早期黄体发育的相关性，2）确定瘦素独立地和直接地刺激黄体血管生成的能力，和3）确定瘦素和OB-Rb在早期发育的CL中的调节。长期目标是促进研究寻找替代治疗黄体缺陷和随后的不孕症的妇女。

DESCRIPTION (provided by applicant): The corpus luteum (CL) is an ovarian structure responsible for the maintenance of pregnancy in mammalian species, via the production of the steroid hormone progesterone. Corpora luteal defects contribute to reproductive abnormalities accounting for approximately 65% of reproductive failures. Abnormal luteal development results in decreased progesterone production and subsequent inability to support a developing fetus. Abnormal/underdeveloped CL's are largely attributed to aberrant angiogenesis. There are many factors known to regulate luteal angiogenesis including vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF-2). All of these factors are produced in ovarian tissue corresponding to periods of high angiogenic activity (ovulatory follicles and CL development), and are regulated by the luteotropic hormone LH (luteinizing hormone). Of interest is the ability of LH to stimulate ovarian follicular production of leptin, a potent satiety hormone predominantly produced in adipose tissue. Leptin is an important metabolic hormone that exhibits both reproductive and angiogenic functional properties. Furthermore, leptin influences the function of VEGF and FGF-2 in non-ovarian tissues. Moreover, the fully functional form of the leptin receptor (OB-Rb) has been identified in developing luteal tissue, which implies that leptin is involved in luteal function. Moreover, preliminary data reported herein shows that leptin upregulates FGF-2 and VEGF in developing CL tissue. This discovery is novel in that numerous studies have attributed leptin's role in the ovary as a regulator in steroidogenic processes. However, leptin's regulatory ability is moderate at best. In addition to leptin's regulation of angiogenic factors, preliminary data reveals that loss of leptin's biological activity increases the frequency of abnormal luteal formation. Hence, the ability of LH to regulate leptin, leptin's ability to regulate angiogenic factors in luteal tissue, and the occurrence of abnormal CL's due to at reduction in bioavailable leptin, suggests that leptin may serve an important role in the development of the CL. Therefore, it is hypothesized that leptin is important for angiogenic processes in the developing CL. The proposed experiments are designed to test the hypothesis and begin to understand the mechanism (s) through which leptin regulates angiogenesis in developing luteal tissue. The specific aims of the study proposed herein are to 1) determine the relevance of leptin to early luteal development in vivo, 2) determine leptin's ability to independently and directly stimulate luteal angiogenesis, and 3) determine the regulation of leptin and OB-Rb in the early developing CL. The long-term goal is to contribute to research searching for alternative treatments regarding luteal defects and subsequent infertility in women.