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The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 7 3377-3386
Copyright © 2001 by The Endocrine Society

Original Articles

Luteal Angiogenesis: Prevention and Intervention by Treatment with Vascular Endothelial Growth Factor TrapA401

Christine Wulff, Helen Wilson, John S. Rudge, Stanley J. Wiegand, Stephen F. Lunn and Hamish M. Fraser

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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