Vascular Endothelial Growth Factor Receptor 2-mediated Angiogenesis is Essential for Gonadotropin-dependent Follicle Development

Overview

Journal J Clin Invest

Specialty General Medicine

Date 2003 Sep 4

PMID 12952915

Citations 33

Authors

Ralf C Zimmermann

Tipton Hartman

Suzanne Kavic

Samuel A Pauli

Peter Bohlen

Mark V Sauer

Jan Kitajewski

Affiliations

Soon will be listed here.

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.

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References

Geva E, Jaffe R . Role of angiopoietins in reproductive tract angiogenesis. Obstet Gynecol Surv. 2000; 55(8):511-9. DOI: 10.1097/00006254-200008000-00024. View

Mcgee E, Hsueh A . Initial and cyclic recruitment of ovarian follicles. Endocr Rev. 2000; 21(2):200-14. DOI: 10.1210/edrv.21.2.0394. View

Hazzard T, Stouffer R . Angiogenesis in ovarian follicular and luteal development. Baillieres Best Pract Res Clin Obstet Gynaecol. 2001; 14(6):883-900. DOI: 10.1053/beog.2000.0133. View

Zimmermann R, Xiao E, Husami N, Sauer M, Lobo R, Kitajewski J . Short-term administration of antivascular endothelial growth factor antibody in the late follicular phase delays follicular development in the rhesus monkey. J Clin Endocrinol Metab. 2001; 86(2):768-72. DOI: 10.1210/jcem.86.2.7181. View

Wulff C, Wiegand S, Saunders P, Scobie G, Fraser H . Angiogenesis during follicular development in the primate and its inhibition by treatment with truncated Flt-1-Fc (vascular endothelial growth factor Trap(A40)). Endocrinology. 2001; 142(7):3244-54. DOI: 10.1210/endo.142.7.8258. View

Zimmermann R, Hartman T, Bohlen P, Sauer M, Kitajewski J . Preovulatory treatment of mice with anti-VEGF receptor 2 antibody inhibits angiogenesis in corpora lutea. Microvasc Res. 2001; 62(1):15-25. DOI: 10.1006/mvre.2001.2312. View

LeCouter J, Kowalski J, Foster J, Hass P, Zhang Z, Dillard-Telm L . Identification of an angiogenic mitogen selective for endocrine gland endothelium. Nature. 2001; 412(6850):877-84. DOI: 10.1038/35091000. View

Zimmermann R, Xiao E, Bohlen P, Ferin M . Administration of antivascular endothelial growth factor receptor 2 antibody in the early follicular phase delays follicular selection and development in the rhesus monkey. Endocrinology. 2002; 143(7):2496-502. DOI: 10.1210/endo.143.7.8896. View

Wulff C, Wilson H, Wiegand S, Rudge J, Fraser H . Prevention of thecal angiogenesis, antral follicular growth, and ovulation in the primate by treatment with vascular endothelial growth factor Trap R1R2. Endocrinology. 2002; 143(7):2797-807. DOI: 10.1210/endo.143.7.8886. View

10.

McConnell N, Yunus R, Gross S, Bost K, Clemens M, Hughes Jr F . Water permeability of an ovarian antral follicle is predominantly transcellular and mediated by aquaporins. Endocrinology. 2002; 143(8):2905-12. DOI: 10.1210/endo.143.8.8953. View

11.

Gomez R, Simon C, Remohi J, Pellicer A . Vascular endothelial growth factor receptor-2 activation induces vascular permeability in hyperstimulated rats, and this effect is prevented by receptor blockade. Endocrinology. 2002; 143(11):4339-48. DOI: 10.1210/en.2002-220204. View

12.

Ferrara N, Gerber H, LeCouter J . The biology of VEGF and its receptors. Nat Med. 2003; 9(6):669-76. DOI: 10.1038/nm0603-669. View

13.

Pedersen T, Peters H . Proposal for a classification of oocytes and follicles in the mouse ovary. J Reprod Fertil. 1968; 17(3):555-7. DOI: 10.1530/jrf.0.0170555. View

14.

Pedersen T . Follicle kinetics in the ovary of the cyclic mouse. Acta Endocrinol (Copenh). 1970; 64(2):304-23. DOI: 10.1530/acta.0.0640304. View

15.

Halpin D, Charlton H . Effects of short-term injection of gonadotrophins on ovarian follicle development in hypogonadal (hpg) mice. J Reprod Fertil. 1988; 82(1):393-400. DOI: 10.1530/jrf.0.0820393. View

16.

Wang X, GREENWALD G . Hypophysectomy of the cyclic mouse. I. Effects on folliculogenesis, oocyte growth, and follicle-stimulating hormone and human chorionic gonadotropin receptors. Biol Reprod. 1993; 48(3):585-94. DOI: 10.1095/biolreprod48.3.585. View

17.

Wang X, GREENWALD G . Hypophysectomy of the cyclic mouse. II. Effects of follicle-stimulating hormone (FSH) and luteinizing hormone on folliculogenesis, FSH and human chorionic gonadotropin receptors, and steroidogenesis. Biol Reprod. 1993; 48(3):595-605. DOI: 10.1095/biolreprod48.3.595. View

18.

Shweiki D, Itin A, Neufeld G, Keshet E . Patterns of expression of vascular endothelial growth factor (VEGF) and VEGF receptors in mice suggest a role in hormonally regulated angiogenesis. J Clin Invest. 1993; 91(5):2235-43. PMC: 288226. DOI: 10.1172/JCI116450. View

19.

Vecchi A, Garlanda C, Lampugnani M, Resnati M, Matteucci C, Stoppacciaro A . Monoclonal antibodies specific for endothelial cells of mouse blood vessels. Their application in the identification of adult and embryonic endothelium. Eur J Cell Biol. 1994; 63(2):247-54. View

20.

Palumbo A, Yeh J . In situ localization of apoptosis in the rat ovary during follicular atresia. Biol Reprod. 1994; 51(5):888-95. DOI: 10.1095/biolreprod51.5.888. View