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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 9 3442-3452
Copyright © 2000 by The Endocrine Society

Original Studies

Progesterone Withdrawal Up-Regulates Vascular Endothelial Growth Factor Receptor Type 2 in the Superficial Zone Stroma of the Human and Macaque Endometrium: Potential Relevance to Menstruation1

Nihar R. Nayak, Hilary O. D. Critchley, Ov D. Slayden, Andreas Menrad, Kristof Chwalisz, David T. Baird and Robert M. Brenner

Oregon Regional Primate Research Center (N.R.N., O.D.S., R.M.B.), Beaverton, Oregon 97006; Center for Reproductive Biology (H.O.D.C., D.T.B.), EH3 9ET Edinburgh, United Kingdom; Schering AG (A.M.), D13342 Berlin, Germany; and Jenapharm (K.C.), 07745 Jena, Germany

Address all correspondence and requests for reprints to: Dr. Robert M. Brenner, Reproductive Sciences, Oregon Regional Primate Research Center, 505 N.W. 185th Avenue, Beaverton, Oregon 97006. E-mail: brennerr{at}ohsu.edu

Several reports indicate that vascular endothelial growth factor (VEGF) expression is increased in endometrial glands and stroma during the menstrual phase in the human endometrium. Here we report that VEGF receptor type 2 (KDR), normally expressed only in the vascular endothelium, was dramatically up-regulated in the stromal cells of the superficial endometrial zones during the premenstrual phase in both human and macaque endometrium. This increase was detectable by Northern analysis, in situ hybridization, and immunocytochemistry and was cell specific, zone specific, cycle phase specific, and VEGF receptor type specific. That is, it only occurred during the premenstrual/menstrual phase, did not occur in glandular epithelium, endothelium, or stromal cells of the deepest endometrial zones, and was not observed for VEGF receptor type 1. The up-regulation of stromal KDR was induced by progesterone (P) withdrawal in both women and macaques, and adding back P 24 h after P withdrawal in macaques blocked stromal, but not vascular, endothelial KDR expression. Promatrix metalloproteinase-1 (MMP-1) was coordinately up-regulated in the same stromal cell population by P withdrawal. Because of reports that VEGF can enhance MMP expression, we hypothesize that VEGF-KDR interactions may influence MMP expression in the superficial zones of the primate endometrium during the premenstrual phase, and that these interactions play a role in the induction of menstruation.




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