Endothelin-2 in Ovarian Follicle Rupture

卵巢卵泡破裂中的内皮素 2

• 批准号: 7077104
• 负责人: CHEMYONG JAY KO
• 金额: $ 24.31万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-15 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7077104
• 关键词: autoradiography; binding sites; corpus luteum; disease /disorder etiology; endothelin; estrogen receptors; female reproductive system disorder; genetically modified animals; hormone metabolism; hormone receptor; hormone regulation /control mechanism; immature animal; immunocytochemistry; in situ hybridization; laboratory mouse; laboratory rat; mature animal; muscle contraction; ovulation; peptides; progesterone receptors; prostaglandins; protein structure function; radioimmunoassay; receptor expression; smooth muscle

DESCRIPTION (provided by applicant): The goal of the proposed studies is to elucidate the mechanism of endothelin-2 (EDN-2) action in follicle rupture. The program of ovulation is activated by a surge of luteinizing hormone, which initiates dramatic changes in molecular, biochemical, and physical aspects of the ovary, eventually leading to rupture of follicles. However, the factors involved in and the mechanism governing the process of follicle rupture are yet to be unveiled. Using a gene expression profiling approach, we have identified EDN-2, a potent smooth muscle constrictor, which is exclusively and transiently expressed in the granulosa cells of periovulatory follicles immediately prior to ovulation. We found that EDN-2 induces rapid and sustained contraction in the ovarian tissue, while tezosentan, an endothelin receptor antagonist, released the contraction. These novel findings led us to hypothesize that EDN-2 directly constricts periovulatory follicles leading to the rupture of the follicle. Supporting the hypothesis, immunohistochemical analysis identified a well-organized smooth muscle layer in the theca externa of each follicle, which forms a sponge-like smooth muscle network at the whole ovarian level. Furthermore, we found that intraovarian injection of tezosentan prior to ovulation completely blocked follicle rupture. In this study, we will elucidate the mechanism of EDN-2 action in follicle rupture. We will determine the target tissues of EDN-2 action, the endothelin receptor subtype(s) that mediates EDN-2 action, and the ovarian concentration of EDN-2. We will also determine the mechanism of endothelin-2 induced follicular constriction in relation to other ovary-produced vasoconstrictive molecules (VIPs, PACAPs, and prostaglandins). In addition, the functional link of progesterone, estrogen, and prostaglandin to the follicle rupture in relation to EDN-2 will be explored. The major strength of this proposal is in the identification of EDN-2 and the ovarian smooth muscle network as the key components of follicle rupture. The novelty of the proposed experiments is the interdisciplinary approaches (genome-wide gene expression profiling, intraovarian injection, and isometric tension measurement). The proposed studies are exceptionally important in order to further our understanding of the mechanism of follicle rupture. The proposed experiments will provide clinical direction in identifying the therapeutic target for the cure of annovulatory symptoms, one of the leading causes of female infertility.

描述（由申请人提供）：拟议研究的目的是阐明内皮素-2 （EDN-2）在卵泡破裂中的作用机制。促黄体激素的激增激活了排卵程序，它引发了卵巢分子、生化和物理方面的巨大变化，最终导致卵泡破裂。然而，卵泡破裂过程的影响因素和机制尚不清楚。使用基因表达谱方法，我们已经鉴定出EDN-2，一种有效的平滑肌收缩剂，在排卵前立即在排卵期卵泡颗粒细胞中短暂表达。我们发现EDN-2在卵巢组织中诱导快速和持续的收缩，而内皮素受体拮抗剂替佐生坦释放收缩。这些新发现使我们假设EDN-2直接收缩排卵周卵泡导致卵泡破裂。免疫组织化学分析支持这一假设，在每个卵泡的外膜中发现了一个组织良好的平滑肌层，它在整个卵巢水平形成海绵状平滑肌网络。此外，我们发现排卵前卵巢内注射替佐生坦完全阻止了卵泡破裂。在这项研究中，我们将阐明EDN-2在卵泡破裂中的作用机制。我们将确定EDN-2作用的靶组织、介导EDN-2作用的内皮素受体亚型以及卵巢中EDN-2的浓度。我们还将确定内皮素-2诱导卵泡收缩的机制与卵巢产生的其他血管收缩分子（vip、pacap和前列腺素）的关系。此外，黄体酮、雌激素和前列腺素在卵泡破裂中的作用与EDN-2的关系也将被探讨。该提案的主要优势在于确定EDN-2和卵巢平滑肌网络是卵泡破裂的关键成分。提出的实验的新颖之处在于跨学科的方法（全基因组基因表达谱，卵巢内注射和等距张力测量）。提出的研究是特别重要的，以进一步了解卵泡破裂的机制。本实验将为确定无排卵症状的治疗靶点提供临床指导，无排卵症状是导致女性不育的主要原因之一。