Much remains to be learned about the periodic menstrual sloughing, bleeding and regenerative repair process so characteristic of the primate endometrium. During the previous research period, the investigator discovered an unexpected involvement of vascular endothelial growth factor (VEGF) and its receptors (R) in the menstrual inductive process. Very early in the premenstrual phase, one of the VEGF receptors, VEGFR-2, also known as KDR, was strongly expressed in the stromal cells (not the vascular endothelium) of the upper endometrial zones, the same cell population that expresses most of the matrix metalloproteinases (MMPs). MMPs are enzymes responsible for the tissue destruction and sloughing associated with menstruation. FLT-1, another VEGF receptor, was also transiently upregulated in the glandular cells which also produce an MMP, called matrilysin. Therefore the investigators hypothesize that VEGF acts through KDR and FLT-1 to facilitate MMP expression in the upper endometrial zones during menstrual induction. Hepatocyte growth factor (HGF) was also expressed transiently in the same endometrial stromal cells at the same time. The investigators hypothesize that HGF and VEGF may interact during the LFT to facilitate MMP upregulation. Keratinocyte growth factor (KGF), a growth factor strongly upregulated by P, had strong trophic effects on the spiral arteries, but the KGF receptor was not detectable in the arteries. The arteries do express KDR and FLT-1, so they hypothesize that KGF acts indirectly through the VEGF system to mediate spiral artery growth under P influence. In the current application they propose to explore the interactions between VEGF, HGF and KGF in the primate endometrium within the following specific aims: 1. The VEGF family and MMPs during menstrual induction. 2. VEFG-HGF interactions in MMP regulation. 3. KGF-VEGF interactions in spiral artery growth. 4. HGF and VEGF antagonists during menstruation.
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