Selected Contribution: Cerebrovascular NOS and cyclooxygenase are unaffected by estrogen in mice lacking estrogen receptor-α

Abstract

Estrogen alters reactivity of cerebral arteries by modifying production of endothelium-dependent vasodilators. Estrogen receptors (ER) are thought to be involved, but the responsible ER subtype is unknown. ER-alpha knockout (alphaERKO) mice were used to test whether estrogen acts via ER-alpha. Mice were ovariectomized, with or without estrogen replacement, and cerebral blood vessels were isolated 1 mo later. Estrogen increased levels of endothelial nitric oxide synthase and cyclooxygenase-1 in vessels from wild-type mice but was ineffective in alphaERKO mice. Endothelium-denuded middle cerebral artery segments from all animals constricted when pressurized. In denuded arteries from alphaERKO but not wild-type mice, estrogen treatment enhanced constriction. In endothelium-intact, pressurized arteries from wild-type estrogen-treated mice, diameters were larger compared with arteries from untreated wild-type mice. In addition, contractile responses to indomethacin were greater in arteries from wild-type estrogen-treated mice compared with arteries from untreated wild-type mice. In contrast, estrogen treatment of alphaERKO mice had no effect on diameter or indomethacin responses of endothelium-intact arteries. Thus ER-alpha regulation of endothelial nitric oxide synthase and cyclooxygenase-1 pathways appears to contribute to effects of estrogen on cerebral artery reactivity.

Effect of estrogen on cerebrovascular prostaglandins is amplified in mice with dysfunctional NOS

“…As we have demonstrated previously in both rats and mice (11,25,40), chronic estrogen treatment results in a significant increase in the levels of cerebrovascular eNOS (Fig. 1A).…”

“…These effects are correlated with an increase in endothelial-dependent vasodilation of the middle cerebral artery (MCA) that is sensitive to the NOS inhibitor N G -nitro-L-arginine methyl ester (L-NAME) (9 -11). Data from transgenic mice indicate that effects of estrogen on cerebrovascular NO are mediated via estrogen receptor (ER)-␣ (11), which is present on cerebral artery endothelium (40).…”

Estrogen receptor α-mediated events promote sex-specific diabetic glomerular hypertrophy

“…Expression of both receptors may alter signaling through ER␣, whereas ER␤ may specifically mediate anti-inflammatory effects (11,12,21,22,26,33). ERs are often coupled into caveolae with nitric oxide synthase in endothelial cells, and both ER␣ and ER␤ have been implicated in the function of a variety of vascular beds (3,7,8,10,32,38). ER␤-deficient mice develop sustained hypertension, and their vascular smooth muscle cells show multiple abnormalities of ion channel function (38).…”

Estradiol Regulation of Prostanoids Production in Endothelium

“…Prostacyclin increased levels after vessel stimulation with estradiol have been mainly associated with enhanced expression of COX-1. In this way, COX-1 protein content is increased in rat (Ospina et al, 2002) and mice (Geary et al, 2001) cerebral blood vessels, and in ovine uterine arteries in response to treatment with estrogen (Rupnow et al, 2002). Indeed, COX-1 (but not COX-2) expression is increased in the endothelium of the ovine uterine artery during the follicular phase of the ovarian cycle and during pregnancy, where estrogen levels are highest (Janowiak et al, 1998;Habermehl et al, 2000).…”

“…The regulatory role of estradiol through ER is supported by other studies. Estradiol increases levels of COX-1 in cerebral blood vessels from wild-type mice but was ineffective in ER knockout mice (Geary et al, 2001) and also increases COX-1 expression through ER in ovine endothelial cells transfected with the human COX-1 promoter (Gibson et al, 2005).…”