Rapid Potentiation of Endothelium-Dependent Vasodilation by Estradiol in Postmenopausal Women Is Mediated via Cyclooxygenase 2

Abstract

Estrogens influence cardiovascular function through direct and indirect effects and via genomic and nongenomic mechanisms. The pathways underlying the nongenomic mechanisms are not completely understood. Estrogen-induced responses in vascular cells have been shown to influence prostaglandins and cyclooxygenase (COX), a key enzyme in the production of prostaglandins, with two isoforms, COX-1 and COX-2. We investigated the effects of prostaglandins on the acute potentiation by 17beta-estradiol (E) of acetylcholine (ACh)-mediated vasodilation in the cutaneous vasculature. Using a double-blind placebo-controlled design, we assessed skin blood flow in 32 healthy, postmenopausal women by laser Doppler velocimetry with direct current iontophoresis of ACh and sodium nitroprusside before and after 6-wk treatment periods with aspirin (a nonspecific COX-1 and COX-2 inhibitor), diclofenac (predominantly a COX-2 inhibitor, which also inhibits COX-1), celecoxib (a specific COX-2 inhibitor), given at anti-inflammatory doses, or placebo. Blood flux values before iontophoresis of ACh did not differ between the treatment groups or after E administration, excluding a direct cutaneous vasodilator effect of the treatments or of E. Acute E administration enhanced the response to ACh after aspirin, diclofenac, and placebo; however, this effect was completely abolished with celecoxib treatment (P < 0.05). E had no effect on sodium nitroprusside-mediated vasodilation after any of the treatments. We conclude that the COX-2 pathway plays a specific role in the rapid E-induced potentiation of cholinergic vasodilation in postmenopausal women.

Endogenous Estrogens Increase Postischemic Hyperemia in the Skin Microcirculation

“…3 On the basis of our and others' previous work investigating the mechanisms involved in postischemic reactive hyperemia of the skin, 8,11 an enhancement of vasodilator prostaglandins may be responsible for the improvement of reactive hyperemia induced by increased estrogen levels in the present study. These mechanisms are different from those in flow-induced dilatation of large peripheral and coronary arteries.…”

Cellular mechanisms underlying the cardiovascular actions of oestrogens

“…However, data on effects of oestrogens on prostanoid synthesis in cultured ECs are conflicting, with one report [52] showing an increase in prostacyclin production in response to E2, and another [53] showing no detectable changes in either basal or agonist-induced prostacyclin release. Interestingly, the rapid potentiation of acetylcholine-induced vasodilation in skin resistance arteries by E2 has been shown to be mediated via COX-2, one of the two isoforms of COX, a key enzyme in prostaglandin synthesis [54].…”

Effects of estrogen on the vascular system

“…It seems that the COX-2 pathway also plays a specific role in estradiol-induced PGI 2 synthesis and vasodilation. In human umbilical vein endothelial cells, 17ß-estradiol increases the release of PGI 2 via the induction of COX-2, but not COX-1 protein (28), and in the cutaneous vasculature of postmenopausal women, acute 17ß-estradiol administration enhanced the response to acetylcholine after aspirin, diclofenac, and placebo, but not after celecoxib treatment (29).…”