NO AND CYCLIC GMP EFFECTS ON GRANULOSA CELL FUNCTIONS

NO 和循环 GMP 对颗粒细胞功能的影响

• 批准号: 6481223
• 负责人: PHILIP S LAPOLT
• 金额: $ 7.33万
• 依托单位: CALIFORNIA STATE UNIVERSITY LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6481223
• 关键词: cyclic GMP; digital imaging; enzyme activity; enzyme induction /repression; follicle stimulating hormone; granulosa cell; hormone biosynthesis; laboratory rat; nitrogen oxides; northern blottings; oogenesis; phosphodiesterases; radioimmunoassay; statistics /biometry; tissue /cell culture

The establishment and maintenance of reproductive competence is dependent upon the influences of many factors act on the ovary. Ovarian functions are highly regulated by the pituitary gonadotropins, follicle- stimulating hormone (FSH) and luteinizing hormone (LH). FSH acts through the second messenger cyclic AMP to induce functional maturation of granulosa cells, associated with increased production of estradiol (E2). In addition to the effects of FSH, granulosa cell maturation is also modulated by other hormones and enzymes, which act through different signal transduction pathways. We have recently demonstrated the inhibitory influences of the major activator of soluble guanylate cyclase, nitric oxide (NO), on FSH-induced aromatase activity. Incubation of granulosa cells with generators of NO inhibits FSH- stimulated estradiol (E2) synthesis, associated with increased levels of cyclic GMP. Interestingly, treatment of granulosa cells with cyclic GMP analogs mimics the inhibitory effects of NO on E2 levels, suggesting a mechanism of NO action and demonstrating the antagonistic effect of cyclic GMP on E2 production. Our most recent findings indicate that NO also attenuates FSH-stimulate cyclic AMP levels in granulosa cells, NO and cyclic GMP on steroidogenesis and signal transduction in rat granulosa cells. However, the mechanisms by which NO and cyclic GMP inhibit FSH-induced E2 and cyclic AMP levels are not known. In addition, little is known regarding the regulated expression of PDEs in the ovary. Therefore, the proposal of FSH on granulosa cell maturation. The findings from these studies will provide important new information regarding the roles of no, cyclic GMP, and PDEs in ovarian functions, and my lead to new clinical approaches related to contraception and infertility treatment.

生殖能力的建立和维持取决于许多因素对卵巢的影响。卵巢功能受到垂体促性腺激素、卵泡刺激素 (FSH) 和黄体生成素 (LH) 的高度调节。 FSH 通过第二信使环 AMP 发挥作用，诱导颗粒细胞功能成熟，从而增加雌二醇 (E2) 的产生。除了 FSH 的影响外，颗粒细胞的成熟还受到其他激素和酶的调节，它们通过不同的信号转导途径发挥作用。我们最近证明了可溶性鸟苷酸环化酶的主要激活剂一氧化氮 (NO) 对 FSH 诱导的芳香酶活性的抑制影响。颗粒细胞与 NO 发生器一起孵育会抑制 FSH 刺激的雌二醇 (E2) 合成，这与环 GMP 水平增加有关。有趣的是，用环 GMP 类似物处理颗粒细胞模拟了 NO 对 E2 水平的抑制作用，提示了 NO 作用机制并证明了环 GMP 对 E2 产生的拮抗作用。我们最新的研究结果表明，NO 还会减弱颗粒细胞中 FSH 刺激的环 AMP 水平，NO 和环 GMP 对大鼠颗粒细胞中类固醇生成和信号转导的影响。然而，NO 和环 GMP 抑制 FSH 诱导的 E2 和环 AMP 水平的机制尚不清楚。此外，关于卵巢中 PDE 的调节表达知之甚少。因此，建议FSH对颗粒细胞成熟的影响。这些研究的结果将提供关于 no、环状 GMP 和 PDE 在卵巢功能中的作用的重要新信息，以及我对与避孕和不孕症治疗相关的新临床方法的研究。