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Vascular endothelial growth factor receptor 2–mediated angiogenesis is essential for gonadotropin-dependent follicle development
Ralf C. Zimmermann, … , Mark V. Sauer, Jan Kitajewski
Ralf C. Zimmermann, … , Mark V. Sauer, Jan Kitajewski
Published September 1, 2003
Citation Information: J Clin Invest. 2003;112(5):659-669. https://doi.org/10.1172/JCI18740.
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Categories: Article Aging

Vascular endothelial growth factor receptor 2–mediated angiogenesis is essential for gonadotropin-dependent follicle development

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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

Ralf C. Zimmermann, Tipton Hartman, Suzanne Kavic, Samuel A. Pauli, Peter Bohlen, Mark V. Sauer, Jan Kitajewski

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Figure 1

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(a) H&E staining of mouse ovaries on experimental day 3. Top panel, ...
(a) H&E staining of mouse ovaries on experimental day 3. Top panel, low-power photomicrographs of three representative whole ovaries from HX animals not treated with hormone (C, control); no advanced antral stage follicles present. Middle panel, low-power photomicrographs of three representative whole ovaries from HX animals stimulated with PMSG (S, stimulation); at least three advanced antral stage follicles present in each section. Lower panel, low-power photomicrographs of three representative whole ovaries from HX animals treated with PMSG plus anti–VEGFR-2 Ab (T, treatment); early antral stage follicles present in each section. (b) Intermediate-power photomicrographs of a control, stimulation, and treatment ovary (boxed area in a). Numbers indicate classes of follicular development. (c) Follicle classification.
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