Compromised aortic vasoreactivity in male estrogen receptor-α-deficient mice during acute lipopolysaccharide-induced inflammation

Activation of the estrogen receptor-alpha( ER alpha) mediates the vasculoprotective effects of estrogen, in part, through modulating nitric oxide ( NO) production and vasodilation. Whereas inflammation is accompanied by altered vascular reactivity and underlies the pathogenesis of vascular disease, the role of the ER alpha in the vascular responses associated with acute systemic inflammation remains poorly characterized. Contractile and relaxation responses of isolated aortic segments were investigated 12 h after ip injection of saline or lipopolysaccharide ( LPS, 10 mg/ kg) in male wild- type ( ER alpha(+/+)) and ER alpha-deficient ( ER alpha(+/+)) mice. As previously observed, LPS- injected ER alpha(+/+) mice displayed reduced contractile responses to phenylephrine and enhanced vasodilation in response to acetylcholine. In contrast, aortic tissues from LPS- injected ER alpha(+/+) mice displayed enhanced contractile responses and reduced sensitivity to acetylcholine- and sodium nitroprusside-induced vasodilation. LPStreatment in ER alpha(+/+) and ER alpha(-/-) mice resulted in similar increased levels of systemic NO production and inducible NO synthase expression in the vascular wall. However, expression of mRNA and protein for endothelial NOS and soluble guanylate cyclase ( alpha- and beta- subunits) were significantly reduced in aortic tissues from LPS- treated ER alpha(-/-) animals, possibly accounting for reduced endothelial NO production and reduced smooth muscle responses to NO. These findings represent new evidence of the functional role of ER alpha in the male vasculature and suggest that during acute LPS- induced inflammatory responses, the ER alpha mediates the sustained expression of the molecular machinery essential for endothelial NO synthesis (i.e. endothelial NOS) and the vascular responses to NO ( i.e. soluble guanylate cyclase).