title: Vascular endothelial growth factor receptor 2-mediated angiogenesis is essential for gonadotropin-dependent follicle development.
abstract: Gonadotropins induce ovarian follicle growth that is coincident with increased follicular vasculature, suggesting a role of angiogenesis in follicle development. Functional studies performed in nonhuman primates show that administration of substances that inactivate VEGF block the development and function of preovulatory follicles as demonstrated by histological analysis or hormone measurements. Blockage of function of VEGF receptor 2 (VEGFR-2) alters follicular hormone secretion, suggesting that the intraovarian effect of VEGF might be mediated by this receptor. The specific mechanism by which follicular development was blocked in these previous studies remains unclear, however. Here we characterize the intraovarian role of VEGFR-2 activity on follicular development by choosing a model in which active feedback is absent, the prepuberally hypophysectomized mouse. Hypophysectomy prevents advanced follicle growth and maturation; however, follicle development to the preovulatory stage can be stimulated by administration of gonadotropins. We report that exogenously administered gonadotropins are unable to drive follicle development to the preovulatory stage in the presence of antiangiogenic agent, VEGFR-2-neutralizing Ab's. This inhibition of follicular development is caused by arrests to both angiogenesis and antrum formation. We conclude that the intraovarian VEGF/VEGFR-2 pathway is critical for gonadotropin-dependent angiogenesis and follicular development.
authors.affiliation: Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA. rcz3@columbia.edu
authors.forename: Ralf C
authors.initials: RC
authors.lastname: Zimmermann
authors.forename: Tipton
authors.initials: T
authors.lastname: Hartman
authors.forename: Suzanne
authors.initials: S
authors.lastname: Kavic
authors.forename: Samuel A
authors.initials: SA
authors.lastname: Pauli
authors.forename: Peter
authors.initials: P
authors.lastname: Bohlen
authors.forename: Mark V
authors.initials: MV
authors.lastname: Sauer
authors.forename: Jan
authors.initials: J
authors.lastname: Kitajewski
mesh_terms: D000818:Animals; D002455:Cell Division; D016228:Endothelial Growth Factors / Q000502:physiology; D004958:Estradiol / Q000096:biosynthesis; D005260:Female; D006064:Gonadotropins, Equine / Q000494:pharmacology*; D007016:Hypophysectomy; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology; D008222:Lymphokines / Q000502:physiology; D051379:Mice; D018919:Neovascularization, Physiologic; D006080:Ovarian Follicle / Q000098:blood supply* / Q000254:growth & development*; D011374:Progesterone / Q000096:biosynthesis; D051381:Rats; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000502:physiology*; D042442:Vascular Endothelial Growth Factors
chemical_list: D016228:Endothelial Growth Factors; D006064:Gonadotropins, Equine; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D011374:Progesterone; D004958:Estradiol; D040301:Vascular Endothelial Growth Factor Receptor-2