Abstract
Objectives. The physiology of the female sexual response and its molecular mediators
remain poorly understood. Nitric oxide (NO) is synthesized in neurons and is a potent
relaxor of vascular and nonvascular smooth muscle. In this study, we hypothesize that
vaginal atrophy and declining sexual function during menopause may be NO dependent.
Using the rat as an experimental model, we examined the expression and topologic localization
of vaginal NO synthase (NOS) and the concomitant induction of apoptosis under normal
and estrogen-depleted conditions.
Methods. Thirty rats were categorized into six groups on the basis of phase of the
estrous cycle or estrogen status after oophorectomy. The expression 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 transferase technique (TUNEL). Trichome staining was performed in all
specimens to determine smooth muscle/collagen ratios.
Results. N-NOS immunoreactivity was localized to nerve fibers supplying vaginal smooth
muscle, perivascular nerve plexuses, and lamina propria. E-NOS was localized 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, levels of both N-NOS and E-NOS declined substantially compared
with those of intact animals, and there was a parallel induction of apoptosis. Estrogen
withdrawal also resulted in increased vaginal atrophy, intramural collagen accumulation,
and perivascular wall thickening, as identified by trichome staining. Estrogen replacement
resulted in a significant increase in E-NOS and N-NOS expression, as well as diminished
apoptosis and vaginal atrophy.
Conclusions. This cellular distribution of NOS in the rat vagina suggests that NO
may modulate both vaginal blood supply and vaginal smooth musculature. Estrogen appears
to play a critical role in concomitantly regulating vaginal NOS expression and apoptosis
in nerves, smooth muscle, vascular endothelium, and epithelium of the rat vagina.
These findings may have significant clinical implications for the pathophysiology
of postmenopausal female sexual dysfunction.
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Article info
Publication history
Accepted:
October 10,
1997
Received in revised form:
October 10,
1997
Received:
February 24,
1997
Footnotes
☆This work has been supported by a Developmental Research Award from the University of Maryland School of Medicine (awarded to N.K.).
Identification
Copyright
© 1998 Elsevier Science Inc. Published by Elsevier Inc. All rights reserved.
