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 stromaduring the
menstrual phase in the human endometrium. Here wereport that VEGF
receptor type 2 (KDR), normally expressed onlyin the vascular
endothelium, was dramatically up-regulated inthe stromal cells of the
superficial endometrial zones duringthe 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. Thatis, it only occurred during the
premenstrual/menstrual phase,did not occur in glandular epithelium,
endothelium, or stromalcells of the deepest endometrial zones, and was
not observedfor VEGF receptor type 1. The up-regulation of stromal KDR
wasinduced by progesterone (P) withdrawal in both women and macaques,
andadding 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 cellpopulation by P withdrawal. Because of reports that VEGF
canenhance MMP expression, we hypothesize that VEGF-KDR interactions
mayinfluence MMP expression in the superficial zones of the primate
endometriumduring the premenstrual phase, and that these interactions
playa role in the induction of menstruation.
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