Abstract
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.
Highlights
Angiogenesis is critical for successful ovulation and formation of the corpus luteum [1]
To examine thrombospondin synthesis and accumulation in the ovulatory follicle, granulosa cells were obtained from monkeys experiencing ovarian stimulation either before (0 h) or 12–36 h after administration of an ovulatory dose of human chorionic gonadotropin (hCG) to span the ovulatory interval in primates
Angiogenesis is an essential component of the ovulatory cascade, since follicular angiogenesis is required for follicle rupture and oocyte release [reviewed in [1]]
Summary
Angiogenesis is critical for successful ovulation and formation of the corpus luteum [1]. Capillaries invade the previously-avascular granulosa cell layer before follicle rupture [3]. Blockade of key vascular growth factor pathways can prevent both ovulation and luteal formation [1] highlighting the close connection between angiogenesis and ovarian function. Thrombospondins are a family of vascular regulators, each containing multiple structure/function domains [4]. Because of these multiple domains, a molecule of thrombospondin can simultaneously interact with cell surface receptors, extracellular matrix components, matrix remodeling proteases, integrins, and growth factors [4, 5].
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