Estrogen modulates paracellular permeability of human endothelial cells by eNOS- and iNOS-related mechanisms

Abstract

Estradiol had a biphasic effect on permeability across cultures of human umbilical vein endothelial cells (HUVEC): at nanomolar concentrations it decreased the HUVEC culture permeability, but at micromolar concentrations it increased the permeability. The objective of the present study was to test the hypothesis that the changes in permeability were mediated by nitric oxide (NO)-related mechanisms. The results revealed dual modulation of endothelial paracellular permeability by estrogen. 1) An endothelial NO synthase (eNOS)-, NO-, and cGMP-related, Ca2+-dependent decrease in permeability was activated by nanomolar concentrations of estradiol, resulting in enhanced Cl−influx, increased cell size, and increases in the resistance of the lateral intercellular space ( R LIS) and in the resistance of the tight junctions ( R TJ); these effects appeared to be limited by the ability of cells to generate cGMP in response to NO. 2) An inducible NO synthase (iNOS)- and NO-related, Ca2+-independent increase in permeability was activated by micromolar concentrations of estradiol, resulting in enhanced Cl−efflux, decreased cell size, and decreased R LIS and R TJ. We conclude that the net effect on transendothelial permeability across HUVEC depends on the relative contributions of each of these two systems to the total paracellular resistance.

Estrogen enhances vasoconstrictive remodeling after injury in male rabbits

“…This proposal agrees with our recent findings that superoxide dismutase replenishment after injury decreases nitrotyrosine levels and rescues bioavailable nitric oxide from inducible nitric oxide synthase (19). Another report showed that micromolar, as opposed to nanomolar, estrogen concentrations used here led to vascular iNOS stimulation and deleterious effects (10). Although accurate estrogen levels could not be documented in our study due to profound interference with the immunoassay, our concentrations were safely below low nanomolar levels (consistent with the observed absence of detection by HPLC at the ~1 µM detection limit; data not shown).…”

Estrogen and Cerebrovascular Physiology and Pathophysiology

“…On the other hand, simple E2 exposure (1 -2 days) was found to increase the expression of iNOS in rat aorta (183) and in cultured endothelial cells (184). However, since these latter data were obtained under conditions not associated with inflammation, their relevance to the present discussion is limited.…”

Endothelial nitric oxide synthase activity is linked to its presence at cell–cell contacts

“…This paradox may be explained either by the different conditions in which NOdependent endothelial permeability was studied or by differences in NO levels. Moderate NO concentrations may decrease permeability, whereas low (in the presence of NOS inhibitor) or high (in the presence of eNOS agonist) levels of NO may increase permeability [51,52]. Interestingly, the role of NO in endothelial permeability has been linked with NO-mediated changes in the cytoskeleton [31,50].…”