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Original Articles |
Medical Research Council Human Reproductive Sciences Unit (C.W., H.W., S.F.L., H.M.F.), Edinburgh, Scotland, United Kingdom EH3 9ET; Regeneron Pharmaceuticals, Inc. (J.S.R., S.J.W.), Tarrytown, New York 10591
Address all correspondence and requests for reprints to: Dr. C. Wulff, Medical Research Council Human Reproductive Sciences Unit, 37 Chalmers Street, Edinburgh, Scotland, United Kingdom EH3 9ET. E-mail c.wulff{at}hrsu.mrc.ac.uk
Abstract
The possibility of stimulating or inhibiting paracrine factors regulating angiogenesis may lead to new approaches for the treatment of pathological conditions of the female reproductive tract. We examined the effects of a clinical candidate, a soluble truncated form of the Flt-1 receptor, vascular endothelial growth factor trapA40 (VEGF trap), in a primate model to determine its ability to prevent the onset of luteal angiogenesis or intervene with the on-going process. Marmosets were treated from the day of ovulation until luteal day 3 (prevention regimen) or on luteal day 3 for 1 day (intervention regimen). Effects of VEGF inhibition were studied by obtaining a proliferation index using bromodeoxyuridine incorporation, quantifying endothelial cell area using CD31, and assessing luteal function by plasma progesterone. After both treatments, intense luteal endothelial proliferation was suppressed, a concomitant decrease in endothelial cell area confirmed the inhibition of vascular development, and a marked fall in plasma progesterone levels showed that luteal function was compromised. In situ hybridization was used to localize and quantify compensatory effects on the expression of angiogenic genes. VEGF messenger ribonucleic acid (mRNA) expression in luteal cells was increased, whereas expression of its receptor, Flt, was decreased. Inhibition of VEGF resulted in localized increased expression of angiopoietin-2 mRNA and its receptor, Tie-2.
The results show that the VEGF trap can prevent luteal angiogenesis and inhibit the established process with resultant suppression of luteal function. Luteal Flt mRNA expression is dependent upon VEGF, and VEGF inhibition results in abortive increases in expression of VEGF, angiopoietin-2, and Tie-2.
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T. Kisliouk, N. Levy, A. Hurwitz, and R. Meidan Presence and Regulation of Endocrine Gland Vascular Endothelial Growth Factor/Prokineticin-1 and Its Receptors in Ovarian Cells J. Clin. Endocrinol. Metab., August 1, 2003; 88(8): 3700 - 3707. [Abstract] [Full Text] [PDF]
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E. D. Albrecht, G. W. Aberdeen, A. L. Niklaus, J. S. Babischkin, D. L. Suresch, and G. J. Pepe Acute Temporal Regulation of Vascular Endothelial Growth/Permeability Factor Expression and Endothelial Morphology in the Baboon Endometrium by Ovarian Steroids J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2844 - 2852. [Abstract] [Full Text] [PDF]
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D. R. Danforth, L. K. Arbogast, S. Ghosh, A. Dickerman, R. Rofagha, and C. I. Friedman Vascular Endothelial Growth Factor Stimulates Preantral Follicle Growth in the Rat Ovary Biol Reprod, May 1, 2003; 68(5): 1736 - 1741. [Abstract] [Full Text] [PDF]
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L. C. Rockwell, S. Pillai, C. E. Olson, and R. D. Koos Inhibition of Vascular Endothelial Growth Factor/Vascular Permeability Factor Action Blocks Estrogen-Induced Uterine Edema and Implantation in Rodents Biol Reprod, December 1, 2002; 67(6): 1804 - 1810. [Abstract] [Full Text] [PDF]
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A. J. Rowe, K. D. Morris, R. Bicknell, and H. M. Fraser Angiogenesis in the Corpus Luteum of Early Pregnancy in the Marmoset and the Effects of Vascular Endothelial Growth Factor Immunoneutralization on Establishment of Pregnancy Biol Reprod, October 1, 2002; 67(4): 1180 - 1188. [Abstract] [Full Text] [PDF]
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T. M. Hazzard, F. Xu, and R. L. Stouffer Injection of Soluble Vascular Endothelial Growth Factor Receptor 1 into the Preovulatory Follicle Disrupts Ovulation and Subsequent Luteal Function in Rhesus Monkeys Biol Reprod, October 1, 2002; 67(4): 1305 - 1312. [Abstract] [Full Text] [PDF]
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R. C. Zimmermann, E. Xiao, P. Bohlen, and M. Ferin Administration of Antivascular Endothelial Growth Factor Receptor 2 Antibody in the Early Follicular Phase Delays Follicular Selection and Development in the Rhesus Monkey Endocrinology, July 1, 2002; 143(7): 2496 - 2502. [Abstract] [Full Text] [PDF]
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C. Wulff, H. Wilson, S. J. Wiegand, J. S. Rudge, and H. M. Fraser Prevention of Thecal Angiogenesis, Antral Follicular Growth, and Ovulation in the Primate by Treatment with Vascular Endothelial Growth Factor Trap R1R2 Endocrinology, July 1, 2002; 143(7): 2797 - 2807. [Abstract] [Full Text] [PDF]
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C. Wulff, H. Wilson, S. E. Dickson, S. J. Wiegand, and H. M. Fraser Hemochorial Placentation in the Primate: Expression of Vascular Endothelial Growth Factor, Angiopoietins, and Their Receptors Throughout Pregnancy Biol Reprod, March 1, 2002; 66(3): 802 - 812. [Abstract] [Full Text] [PDF]
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