Paper Presentations: AUGS Abstracts: 2005 26th Annual Scientific Meeting of The American Urogynecologic Society
Lysyl oxidases are copper-dependent amine oxidases produced by activated smooth muscle cells and fibroblasts. Mammals have up to five potential LOX family members (lysyl oxidase (LOX), and lysyl oxidase-like (LOXL) proteins 1 through 4). These enzymes play a vital role in the extracellular cross-linking and stabilization of collagen and elastin both in development and in response to injury. Recently, it was reported that LOXL1 knockout mice develop pelvic organ prolapse. The goal of this investigation was to determine the regulation of LOX and LOXL1 in vaginal tissues from nonpregnant and pregnant mice and correlate these changes with remodeling of the vaginal extracellular matrix (ECM) during pregnancy.
Real-time PCR was used to quantify mRNA for LOX and LOXL1 in vaginal tissues from ovariectomized, nonpregnant, pregnant, parturient, and postpartum mice (n=4–8 at each time point). Messenger RNA levels were expressed relative to β-2 microglobulin. To determine the hormonal regulation of LOX in the vagina, mice were ovariectomized and treated with vehicle, 17β-estradiol (E2, 50 μg/kg), progesterone (P, 1 mg/d), or E2+P for 3 days. In paired animals, Masson's trichrome and elastic fiber staining was performed.
Early in pregnancy (d8-10), expression of LOX decreased 8- to 10-fold in the vagina, and remained suppressed throughout gestation. LOX mRNA, but not LOXL1, in the vagina increased significantly in labor and 12–36 hours postpartum. Changes in LOX mRNA were accompanied by matrix remodeling in the vaginal wall. While the matrix of the vaginal wall in nonpregnant mice was characterized by dense well-organized collagen bundles and numerous elastic fibers suspending the muscularis to the basal lamina of the vaginal epithelium, the intensity of collagen staining progressively decreased during pregnancy. Decreased collagen density, increased interstitial edema, and dissolution of the ECM were maximal 2–6 hours after delivery. Reorganization of the matrix occurred by 48 hours postpartum. Expression of LOX was decreased 25-fold in vagina from ovariectomized compared with nonpregnant cycling mice. E2 treatment resulted in significant increases in LOX mRNA (0.04 ± 0.01 to 0.61 ± 0.12, P≤0.01), whereas progesterone inhibited estrogen-induced increases in LOX mRNA (0.33 ± 0.15).
The vaginal muscularis undergoes dynamic changes during pregnancy characterized by remodeling of the ECM and decreased expression of lysyl oxidase. Estrogen may regulate cross-linking of collagen and elastin in the vaginal muscularis through increased transcription of LOX. On the other hand, suppression of LOX by high levels of progesterone during pregnancy or by low levels of estrogen after menopause may contribute to decreased formation of collagen and elastin in the extracellular matrix of the vagina.