Estrogen modulation of epithelial permeability in cervical-vaginal cells of premenopausal and postmenopausal women.

An important role of estrogen is regulation of epithelial permeability and the control of fluid transudation into the cervical and vaginal lumens. Our present understanding of transepithelial transport in relatively leaky types of epithelia, such as the cervical and vaginal epithelia, is based on the pioneering works of Ussing and Zerahn1 and Spring and Hope.2 The Ussing-Zerahn model predicts that luminal fluids are derived from the blood compartment; that plasma moves through the epithelial paracellular (intercellular) space (Fig. 1B), and that paracellular transport of the fluid is controlled by the resistance of the epithelial tight junctions (RTJ) and of the epithelial lateral intercellular space (RLIS). The RTJ and the RLIS contribute in series to the total resistance (RTE) so that RTE ≈ RTJ + RLIS. The RTJ is a relatively high resistance and is determined by occlusion of the intercellular space through the interactions of extracellular loops of transcellular tight junctional proteins such as the claudins3 and occludin4 (Fig. 1D-E). The RLIS is considered a low transepithelial resistance and is determined by the proximity of neighboring epithelial cells (Fig. 1A). The Spring-Hope model2 predicts that the driving force moving the fluid from the blood into the lumen is the capillary blood pressure, which creates a subluminal to luminal hydrostatic gradient (Fig. 1A and B). Subluminal to luminal hydrostatic gradients dilate the lateral intercellular space, thereby decreasing the RLIS (Fig. 1B). Dilation is restricted to the basolateral intercellular space because of the apical location of adherens intercellular junctions, which prevent lateral separation near the apical regions of the cells (Fig. 1B). FIG. 1 Models of estrogen regulation of transepithelial permeability. A: The main resistances for free diffusion of fluid from the capillary bed into the lumen through the paracellular (intercellular) space are the tight junctional resistance (RTJ) and the resistance ... Estrogen increases fluid transudation by a number of known mechanisms. Estrogen decrease in capillary resistance increases blood flow, which would tend to increase the subluminal to luminal hydrostatic gradient (Fig. 1C).5 However, this effect contributes relatively little to net fluid transudation,6,7 and the main estrogenic control of transepithelial transport is by modulation of epithelial permeability through regulation of the RTJ (Fig. 1C-E) and the RLIS (Fig. 1C, F, G). Estrogen decrease in RTJ is thought to be mediated by matrix metalloproteinase-7-dependent modulation of occludin,8-10 and the decrease in RTJ is explained by loss of gating of the intercellular space due to degradation of occludin extracellular loops.10 Estrogen decrease in the RLIS involves at least three known molecular mechanisms: actin depolymerization and the formation of monomeric-dominated G-actin cytoskeleton11; decreased dimerization of nonmuscle myosin type II-B (NMMII-B), the predominant cytoskeletal epithelial myosin12,13; and increased magnesium-adenosine triphosphatase (MgATPase) activity of the NMMII-B.14 Collectively the actin and NMMII-B effects of estrogen would tend to fragment the cortical actomyosin ring and induce formation of a dynamic cytoskeleton (Fig. 1E-G). This would facilitate dilation of the basolateral intercellular space (ie, decrease the RLIS) in response to the capillary subluminal to luminal hydrostatic gradients (Fig. 1C). The objectives of the present study were to better understand estrogen modulation of the RTJ and RLIS and how menopause affects estrogen actions. The results revealed that estrogen increases epithelial permeability by inducing an early transient decrease in RLIS followed by a slower persistent decrease in RTJ. The potency of estrogen actions was similar in cells of premenopausal and postmenopausal women, but the effects on NMMII-B filamentation and MgATPase activity were shorter in cells of postmenopausal women, resulting in faster reversal of the decrease in RLIS.