Department of Obstetrics and Gynecology, University of Kentucky, Lexington, Kentucky.
Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, Virginia.
Endocrinology. 2018 Jun 1;159(6):2447-2458. doi: 10.1210/en.2018-00020.
The luteinizing hormone (LH) surge is essential for ovulation, but the intrafollicular factors induced by LH that mediate ovulatory processes (e.g., angiogenesis) are poorly understood, especially in women. The role of secretogranin II (SCG2) and its cleaved bioactive peptide, secretoneurin (SN), were investigated as potential mediators of ovulation by testing the hypothesis that SCG2/SN is induced in granulosa cells by human chorionic gonadotropin (hCG), via a downstream LH receptor signaling mechanism, and stimulates ovarian angiogenesis. Humans, nonhuman primates, and rodents were treated with hCG in vivo resulting in a significant increase in the messenger RNA and protein levels of SCG2 in granulosa cells collected early during the periovulatory period and just prior to ovulation (humans: 12 to 34 hours; monkeys: 12 to 36 hours; rodents: 4 to 12 hours post-hCG). This induction by hCG was recapitulated in an in vitro culture system utilizing granulosa-lutein cells from in vitro fertilization patients. Using this system, inhibition of downstream LH receptor signaling pathways revealed that the initial induction of SCG2 is regulated, in part, by epidermal growth factor receptor signaling. Further, human ovarian microvascular endothelial cells were treated with SN (1 to 100 ng/mL) and subjected to angiogenesis assays. SN significantly increased endothelial cell migration and new sprout formation, suggesting induction of ovarian angiogenesis. These results establish that SCG2 is increased in granulosa cells across species during the periovulatory period and that SN may mediate ovulatory angiogenesis in the human ovary. These findings provide insight into the regulation of human ovulation and fertility.
促黄体生成素 (LH) 激增对于排卵至关重要，但 LH 诱导的卵泡内因子（如血管生成）介导排卵过程的机制尚不清楚，尤其是在女性中。本研究通过测试以下假说，即 SCG2/SN 通过下游 LH 受体信号机制在人绒毛膜促性腺激素 (hCG) 的作用下被颗粒细胞诱导，并刺激卵巢血管生成，来研究分泌颗粒蛋白 II (SCG2) 及其裂解的生物活性肽分泌素 (SN) 是否作为排卵的潜在介质。通过体内给予 hCG 处理人类、非人类灵长类动物和啮齿动物，在排卵前的早期（人类：12 至 34 小时；猴子：12 至 36 小时；啮齿动物：4 至 12 小时），发现颗粒细胞中的 SCG2 的信使 RNA 和蛋白水平显著增加。该 hCG 诱导作用可在利用体外受精患者的颗粒细胞 - 黄体细胞的体外培养系统中重现。使用该系统，抑制下游 LH 受体信号通路表明，SCG2 的初始诱导部分受表皮生长因子受体信号的调节。此外，用 SN（1 至 100ng/mL）处理人卵巢微血管内皮细胞，并进行血管生成测定。SN 显著增加了内皮细胞的迁移和新芽形成，提示诱导卵巢血管生成。这些结果表明，在排卵前周期内，SCG2 在各种物种的颗粒细胞中增加，并且 SN 可能介导人类卵巢中的排卵血管生成。这些发现为人类排卵和生育能力的调节提供了新的见解。
