Sex differences in endothelium-dependent vasodilator signals (NO and EDH) in the progression of vascular disease

Abstract

Female appears to have a lower risk of developing vascular diseases compared to age-matched male, until after menopause. Vascular diseases, in particular atherosclerosis, develop with aging, hypertension and hyperlipidemia, and are associated with an impaired capacity of the endothelium to generate vasodilator signals. The major endothelium-derived vasodilator signals are nitric oxide (NO) and endothelium-dependent hyperpolarization (EDH); in conduit arteries, the former plays a predominant role in the regulation of vascular tone, while the contribution of the latter increases as the diameter of the arteries decreases. In superior mesenteric arteries of young (8 to 10 weeks old) rats, both NO- and EDH-type relaxations are greater in females than in males. Long-term administration of the major female sex hormone 17β-estradiol to ovariectomized female rats improves EDH-type relaxations. During aging (from 8 to 28 weeks of age), without or with concomitant hyperlipidemia, NO- and EDH-type relaxations are impaired in mesenteric arteries of male rodents; the impairments are not observed in female counter-parts or in male arteries exposed to 17β-estradiol. The acute beneficial vascular effects of 17β-estradiol are mimicked by the antioxidant apocynin. In aortae of hypertensive rats, 17β-estradiol acutely increases the activation of epidermal growth factor receptor and endothelial nitric oxide synthase; these effects can be mimicked by the phytoestrogen genistein. Taken in conjunction, the female sex hormone accounts, at least partly, for the sex differences with ageing or during the progression of vascular disease. An understanding of the mechanism underlying the beneficial vascular effect of estrogen may help identifying effective pharmacological strategies to prevent the progression of vascular complications of different etiology in males, as well as in postmenopausal females.