Preovulatory treatment of mice with anti-VEGF receptor 2 antibody inhibitsangiogenesis in corpora lutea

Adult mammalian angiogenesis occurs predominantly in female reproductive or gans: the ovary and the uterus. Angiogenesis is very active during corpus l uteum formation. A key regulator of angiogenesis is vascular endothelial gr owth factor (VEGF), which is highly expressed during corpus luteum formatio n. Inhibition of VEGF activity can block the formation and function of the corpora lutea by preventing angiogenesis, The VEGF receptor 2 (VEGF-R2) med iates the angiogenic action of VEGF and is expressed during corpus luteum f ormation. We hypothesized that treatment with an antibody against VEGF-R2 w ould inhibit luteal angiogenesis by blocking VEGF/VEGF-R2 interaction. Imma ture mice were induced to superovulate with PMSG/hCG resulting in neovascul arization in the corpora lutea, as evidenced by abundant staining for the e ndothelial-specific adhesion molecule PECAM, Multiple doses of a monoclonal antibody against the VEGF-R2 (DC101) were administered to immature mice. T reatment was initiated 2 days prior to the induction of superovulation with PMSG/hCG. This antibody inhibited luteal angiogenesis as evidenced by the lack of PECAM staining in the center of the corpora lutea. Multiple dose tr eatment with antibody initiated prior to gonadotropin administration could not dissociate the luteal inhibition from the consequences of inhibition of angiogenesis in the developing follicle. Administration of a single, preov ulatory dose of anti-VEGF-R2 antibody, such that follicular angiogenesis wo uld not be affected, also inhibited luteal development, demonstrating that luteal angiogenesis is required for corpus luteal development, We conclude that VEGF acting through VEGF-R2 has an obligatory role in luteal angiogene sis and corpus luteum formation. (C) 2001 Academic Press.