Thrombospondin 1 (THBS1) Promotes Follicular Angiogenesis, Luteinization, and Ovulation in Primates
Thrombospondin 1 (THBS1) Promotes Follicular Angiogenesis, Luteinization, and Ovulation in Primates
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DOI：
10.3389/fendo.2019.00727
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发表时间：
2019-11-07
影响因子：
5.2
通讯作者：
Duffy, Diane M.
中科院分区：
文献类型：
--
作者：
Bender, Hannah R.;Campbell, Genevieve E.;Duffy, Diane M.
血管生成对于排卵和黄体的形成至关重要。糖蛋白的血小板反应蛋白 (THBS) 家族在血管生成的调节中发挥着多种作用，但这些血管调节因子在排卵和黄体化中的作用仍有待阐明。使用食蟹猴作为人类排卵模型，我们证明排卵前卵泡颗粒细胞中 THBS1 mRNA 和蛋白质的水平在排卵促性腺激素激增后增加，并在预期排卵时间之前达到峰值水平。 THBS1 体外处理猴卵巢微血管内皮细胞可刺激迁移、增殖和毛细血管芽形成，这与 THBS1 的促血管生成作用一致。与注射 IgG 的对照卵泡相比，向猴子排卵前卵泡注射抗 THBS1 抗体可降低卵泡破裂率和响应排卵促性腺激素刺激的卵母细胞释放率。有趣的是，来自注射抗 THBS1 抗体的卵泡的三个卵母细胞中的两个是完整的生发囊泡，表明减数分裂未能按预期恢复。与注射对照 IgG 的卵泡相比，注射抗 THBS1 抗体的卵泡还显示出颗粒细胞层扩张、内皮细胞侵袭和毛细血管形成减少。总的来说，这些发现支持 THBS1 在卵泡血管生成中的关键作用，对成功排卵和黄体形成都有影响。
Angiogenesis is essential to both ovulation and the formation of the corpus luteum. The thrombospondin (THBS) family of glycoproteins plays diverse roles in regulation of angiogenesis, but the role of these vascular regulators in ovulation and luteinization remain to be elucidated. Using the cynomolgus macaque as a model for human ovulation, we demonstrated that levels of THBS1 mRNA and protein in preovulatory follicle granulosa cells increased after the ovulatory gonadotropin surge, with peak levels just before the expected time of ovulation. THBS1 treatment of monkey ovarian microvascular endothelial cells in vitro stimulated migration, proliferation, and capillary sprout formation, consistent with a pro-angiogenic action of THBS1. Injection of an anti-THBS1 antibody into monkey preovulatory follicles reduced rates of follicle rupture and oocyte release in response to an ovulatory gonadotropin stimulus when compared with control IgG-injected follicles. Interestingly, two of three oocytes from anti-THBS1 antibody injected follicles were germinal vesicle intact, indicating that meiosis failed to resume as anticipated. Follicles injected with anti-THBS1 antibody also showed reduced granulosa cell layer expansion, endothelial cell invasion, and capillary formation when compared to control IgG-injected follicles. Overall, these findings support a critical role for THBS1 in follicular angiogenesis, with implications for both successful ovulation and corpus luteum formation.