The key role of caveolin-1 in estrogen-mediated regulation of endothelial nitric oxide synthase function in cerebral arterioles in vivo

The marked impairment in cerebrovascular endothelial nitric oxide synthase (eNOS) function that develops after ovariectomy may relate to the observati on that the abundance of cerebral vascular eNOS and its endogenous inhibito r, caveolin-1, vary in opposite directions with chronic changes in estrogen status. The authors endeavored, therefore, to establish a link between the se correlative findings by independently manipulating, in ovariectomized fe male rats, eNOS and caveolin-1 expression, while monitoring agonist (acetyl choline)stimulated eNOS functional activity. In the current study, the auth ors showed that individually neither the up-regulation of eNOS (through sim vastatin treatment), nor the down-regulation of caveolin-1 (through antisen se oligonucleotide administration) is capable of restoring eNOS function in pial arterioles in vivo in these estrogen-depleted rats. Only when eNOS up regulation and caveolin-1 down-regulation are combined is activity normaliz ed. These results establish a mechanistic link between the estrogen-associa ted divergent changes in the abundance of caveolin-1 and eNOS protein and e NOS functional activity in cerebral arterioles.