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Estrogen Enhances Cystatin C Expression in the Macaque Vagina

Oregon National Primate Research Center (O.D.S., K.H., R.S.C., R.M.B.), Beaverton, Oregon 97006; and Division of Urogynecology and Reconstructive Pelvic Surgery (L.N.O., A.L.C.), Oregon Health and Science University, Portland, Oregon 97239

Address all correspondence and requests for reprints to: Ov D. Slayden, Ph.D., Division of Reproductive Sciences, Oregon National Primate Research Center, 505 NW 185th Avenue, Beaverton, Oregon 97006. E-mail: slaydeno{at}ohsu.edu.

Cystatin C is a secreted inhibitor of cysteine proteinases that participates in extracellular matrix remodeling. Whether hormones affect its expression in the vagina was unknown. Consequently, we examined the effects of estradiol (E₂), progesterone (P), and raloxifene on vaginal cystatin C in rhesus macaques. In experiment 1, ovariectomized animals were treated sequentially with E₂ (14 d) and E₂ + P (14 d) to induce 28-d menstrual cycles. Vaginal samples were collected on d 6, 8, 14, and 28 of the induced cycle. Some cycled animals were deprived of both E₂ + P for 28 d. In experiment 2, ovariectomized animals were treated for 5 months with E₂ alone, E₂ + P, raloxifene, or left untreated. Total RNA from the vaginal wall was analyzed for the cystatin C transcript with a commercially prepared cDNA array and semiquantitative RT-PCR. Vaginal cryosections were analyzed by in situ hybridization for cystatin C transcript and by immunocytochemistry for the protein. E₂ treatment significantly (5-fold; P < 0.05) increased expression of cystatin C transcript over the levels in the hormone-deprived controls, and cotreatment with P (E₂ + P) blocked this effect. Raloxifene treatment did not affect cystatin C expression. In situ hybridization and immunocytochemistry revealed that cystatin C was localized in fibroblasts and smooth muscle cells throughout the vaginal wall but not in smooth muscle cells of arteries or levator ani myocytes. In summary, E₂ increased vaginal cystatin C expression in the fibroblasts and smooth muscle bundles, P suppressed this effect, and raloxifene had no effects on cystatin C. Elevated cystatin C, by suppressing cysteine proteinase activity, may strengthen the vaginal wall and mitigate the potential for pelvic floor prolapse.

This work was supported by National Institutes of Health Grants RR00163 (to O.D.S. and R.M.B.), HD38673 (to A.L.C.), HD01243 (to L.N.O.), and U54 HD 18185 as part of the Specialized Cooperative Centers Program in Reproduction Research.

Abbreviations: E₂, Estradiol; ECM, extracellular matrix; ER, estrogen receptor; ICC, immunocytochemistry; ISH, in situ hybridization; MMP, matrix metalloproteinase; P, progesterone; SERM, selective estrogen receptor modulator; SSC, saline sodium citrate.

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