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 menstruation

Several reports indicate that vascular endothelial growth factor (VEGF) exp ression is increased in endometrial glands and stroma during the menstrual phase in the human endometrium. Here we report that VEGF receptor type 2 (K DR), normally expressed only in the vascular endothelium, was dramatically up-regulated in the stromal cells of the superficial endometrial zones duri ng the premenstrual phase in both human and macaque endometrium. This incre ase was detectable by Northern analysis, in situ hybridization, and immunoc ytochemistry and was cell specific, zone specific, cycle phase specific, an d VEGF receptor type specific. That is, it only occurred during the premens trual/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 upregulation of stromal KDR was induced by proge sterone (P) withdrawal in both women and macaques, and adding back P 24 h a fter P withdrawal in macaques blocked stromal, but not vascular, endothelia l KDR expression. Promatrix metalloproteinase-l (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 p rimate endometrium during the premenstrual phase, and that these interactio ns play a role in the induction of menstruation.