ROLE OF STROMAL AND EPITHELIAL ESTROGEN-RECEPTORS IN VAGINAL EPITHELIAL PROLIFERATION, STRATIFICATION, AND CORNIFICATION

Estradiol 17-beta (E-2) induces epithelial proliferation, stratificati on, and cornification in vaginal epithelium. Our aim was to determine the respective roles of epithelial and stromal estrogen receptor-alpha (ER alpha) in these E-2-induced events. Vaginal epithelium (E) and st roma (S) from adult ER alpha knockout (ko) and wild-type (wt) neonatal Balb/c mice were enzymatically separated and used to produce four typ es of tissue recombinants in which epithelium, stroma, or both lack fu nctional ERa. Tissue recombinants were grafted into female nude mice, which were subsequently ovariectomized and treated with oil or E,. In response to E, treatment, grafts prepared with wt-S (wt-S + wt-E and w t-S + ko-E) showed similar large increases in epithelial labeling inde x, indicating that E, stimulated epithelial proliferation despite a la ck of epithelial ERa in wt-S + ko-E tissue recombinants. Conversely, i n tissue recombinants prepared with ko-S (ko-S + wt-E and ko-S + ko-E) , epithelial labeling index remained at baseline levels after E-2 or o il treatment, even though epithelial ER alpha were detected in ko-S wt-E grafts. Epithelial cornification was present in wt-S + wt-E graft s from E-2-treated hosts, whereas epithelium in all other tissue recom binants failed to cornify. Grafts composed of wt-S + wt-E from E-2-tre ated hosts had highly stratified epithelium, whereas epithelial thickn ess was reduced almost 60% in wt-S + ko-E tissue recombinants grown in E-2-treated hosts and was atrophic in all other tissue recombinants. In addition, cytokeratin 10, a marker of epithelial differentiation, w as strongly expressed in wt-S + wt-E tissue recombinants grown in E-2- treated hosts but was markedly reduced or absent in all other tissue r ecombinants. These results indicate that E-2-induced vaginal epithelia l proliferation is mediated indirectly through stromal ER alpha, consi stent with our recent findings in uterus. Conversely, both epithelial and stromal ER alpha are required for E-2 induced cornification and no rmal epithelial stratification. These are the first known functions at tributed to epithelial ER alpha in vivo and the first time any epithel ial response to E-2 has been shown to involve both stromal and epithel ial ER alpha.