EFFECT OF ESTROGEN WITHDRAWAL ON NITRIC-OXIDE SYNTHASE EXPRESSION ANDAPOPTOSIS IN THE RAT VAGINA

Objectives. The physiology of the female sexual response and its molec ular mediators remain poorly understood. Nitric oxide (NO) is synthesi zed in neurons and is a potent relaxer of vascular and nonvascular smo oth muscle. In this study, we hypothesize that vaginal atrophy and dec lining sexual function during menopause may be NO dependent. Using the rat as an experimental model, we examined the expression and topologi c localization of Vaginal NO synthase (NOS) and the concomitant induct ion of apoptosis under normal and estrogen-depleted renditions. Method s. Thirty rats were categorized into six groups on the basis of phase of the estrous cycle or estrogen status after oophorectomy. The expres sion and cellular localization of NOS was examined in frozen sections using specific antibodies against neuronal (N-NOS) and endothelial NOS (E-NOS). Apoptotic cells were identified in situ using the terminal t ransferase technique (TUNEL). Trichome staining was performed in all s pecimens to determine smooth muscle/collagen ratios. Results, N-NOS im munoreactivity was localized to nerve fibers supplying vaginal smooth muscle, perivascular nerve plexuses, and lamina propria, E-NOS was loc alized to Vascular endothelium and perivascular smooth muscle fibers. Both E-NOS and N-NOS expression in intact cycling animals was highest during proestrous and lowest during metestrous. After oophorectomy, le vels of both N-NOS and E-NOS declined substantially compared with thos e of intact animals, and there was a parallel induction of apoptosis. Estrogen withdrawal also resulted in increased vaginal atrophy, intram ural collagen accumulation, and perivascular wall thickening, as ident ified by trichome staining, Estrogen replacement resulted in a signifi cant increase in E-NOS and N-NOS expression, as well as diminished apo ptosis and vaginal atrophy. Conclusions. This cellular distribution of NOS in the rat vagina suggests that NO may modulate both vaginal bloo d supply and vaginal smooth musculature, Estrogen appears to play a cr itical role in concomitantly regulating Vaginal NOS expression and apo ptosis in nerves, smooth muscle, vascular endothelium, and epithelium of the rat vagina. These findings may have significant clinical implic ations for the pathophysiology of postmenopausal female sexual dysfunc tion. (C) 1998, Elsevier Science Inc. All rights reserved.