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Estrogen has been shown to affect vascular cell and arterial function in vitro and in vivo. Here we examined the ability of estradiol (E₂) to cause rapid arterial dilation of elastic and muscular arteries in vivo and the mechanisms involved. E₂ administration caused a rapid increase in the outer wall diameter of both types of arteries in ovariectomized female mice. This resulted from estrogen receptor (ER)-mediated stimulation of nitric oxide production, demonstrated by preinjecting the mice arteries with a soluble inhibitor of nitric oxide (monomethyl l-arginine) and by showing the absence of E₂ action in eNOS-/- mice. Rapid activation of both ERK/MAP kinase and phosphatidylinositol 3-kinase activity was found in the E₂-exposed arteries, and inhibiting either kinase prevented the vasodilatory action of E₂. Kinase activation and vasodilator responses to E₂ were absent in either ERα or ERβ knock-out mice, implicating …