HORMONAL CONTROL OF FEMALE REPRODUCTIVE TRACT

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This research aims to increase our understanding of the stromal-epithelial interactions that mediate the action of steroids in the reproductive tract. Our studies focus on the regulation and effects of specific growth factors, and on specific enzymes called matrix metalloproteinases (MMPs). Our studies have progressed in three main areas. First, we have characterized two novel forms of hepatocyte growth factor (HGF) expressed in the macaque endometrium. These two truncated transcripts of HGF are similar to two variants (HGF/NK1 and HGF/NK2 ) that are reported for the human genome. Northern blot of total RNA from microdissected, estradiol-treated endometrium showed that HGF/SF mRNA was expressed at 10 fold higher levels in the functionalis than in the basalis zone. In situ hybridization confirmed this expression gradient and showed that specific signal was confined to the subepithelial and perivascular stromal cells. Second, we immunocytochemically localized expr ession of two forms of vascular endothelial growth factor (VEGF) receptor, Type I (FLT1) and Type II (flk1/KDR) in the macaque endometrium. FLT1 staining was detected on the endothelial surface of small vessels and muscles of larger spiral arteries. Arterial staining was strongest in monkeys treated with estradiol plus progesterone (E2 + P), suggesting that VEGF may play a role during luteal phase artery growth. KDR staining was also evident in vascular endothelial cells. However, when P was withdrawn at the end of the cycle, a wave of strong KDR staining was observed in the stromal cells of the upper functionalis zone. KDR in stromal cells may play a functional role in remodeling the endometrium at the end of the menstrual cycle. Third, a critical period of P withdrawal is required to induce menstruation. We have evaluated expression of various matrix metalloproteinases (MMPs) during and after the critical period. When P is replaced during the critical period, expression of M MP-1, MMP-2, MMP-3, and TIMP 1 are blocked. However, when P is replaced after the critical period, some but not all MMPs are blocked. This indicates that MMPs vary both in their sensitivity to P suppression and their importance in menstruation. FUNDING NIH HD19182 PUBLICATIONS Lindsey JS, Brenner RM. Rhesus macaque endometrium expresses two novel transcripts of hepatocyte growth factor/scatter factor. Biol Reprod (Suppl 1) 58:173 (abstract 324). Lindsey JS, Slayden OD, Brenner RM. A zonal gradient of hepatocyte growth factor/scatter factor expression in rhesus macaque endometrium. Mol Biol Cell 9:477a,1998 (abstract). Rudolph-Owen LA, Slayden OD, Matrisian LM, Brenner RM. Matrix metalloproteinase expression in Macaca mulatta endometrium Evidence for zone-specific regulatory tissue gradients. Biol Reprod 59:1349-1359, 1998.