Endothelin-2 in Ovarian Follicle Rupture

本研究旨在阐明内皮素-2(EDN-2)在卵泡中的作用机制。 破裂。排卵程序是由黄体生成素的激增激活的，这启动了戏剧性的 卵巢的分子、生化和生理方面的变化，最终导致卵巢破裂 毛囊。然而，卵泡破裂过程中涉及的因素和机制尚不清楚。 即将揭开面纱。使用基因表达谱方法，我们已经鉴定出一种有效的平滑因子EDN-2 肌肉收缩蛋白，它仅在排卵周围的颗粒细胞中瞬时表达 排卵前的卵泡。我们发现EDN-2可诱导心肌细胞快速持续收缩。 卵巢组织，而内皮素受体拮抗剂替佐生则释放收缩。这些小说 这些发现导致我们假设EDN-2直接收缩排卵周卵泡，导致卵泡破裂 卵泡。支持这一假说的免疫组织化学分析发现， 在每个卵泡的外膜中的肌层，在每个卵泡的 整个卵巢水平。此外，我们还发现，排卵前卵巢内注射替佐生 完全阻断卵泡破裂。在本研究中，我们将阐明EDN-2在卵泡中的作用机制。 破裂。我们将确定EDN-2作用的靶组织，内皮素受体亚型(S) 介导EDN-2的作用，以及卵巢中EDN-2的浓度。我们还将确定 内皮素-2引起的卵泡收缩与卵巢产生的其他血管收缩分子的关系 (VIP、PACAP和前列腺素)。此外，黄体酮、雌激素和雌激素的功能联系 将探讨前列腺素与卵泡破裂与EDN-2的关系。这项建议的主要优点是 是在鉴定EDN-2和卵巢平滑肌网为卵泡的关键成分 破裂。提出的实验的新颖性在于跨学科的方法(全基因组基因 表达谱、卵巢内注射和等长张力测量)。建议进行的研究包括 为了加深我们对卵泡破裂机制的理解，这一点尤为重要。这个 建议的实验将为确定治愈的治疗靶点提供临床指导 烦躁症状，女性不孕的主要原因之一。

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 vasoconstrice 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 interdisplinary approachs (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.