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

Estradiol had a biphasic effect on permeability across cultures of human um bilical vein endothelial cells (HUVEC): at nanomolar concentrations it decr eased the HUVEC culture permeability, but at micromolar concentrations it i ncreased the permeability. The objective of the present study was to test t he hypothesis that the changes in permeability were mediated by nitric oxid e (NO)related mechanisms. The results revealed dual modulation of endotheli al paracellular permeability by estrogen. 1) An endothelial NO synthase (eN OS)-, NO-, and cGMP-related, Ca2+-dependent decrease in permeability was ac tivated by nanomolar concentrations of estradiol, resulting in enhanced Cl- influx, increased cell size, and increases in the resistance of the latera l 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 gen erate cGMP in response to NO. 2) An inducible NO synthase (iNOS)- and NO-re lated, Ca2+-independent increase in permeability was activated by micromola r 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 contrib utions of each of these two systems to the total paracellular resistance.