Improvement of Endothelial Dysfunction by Selective Estrogen Receptor-α Stimulation in Ovariectomized SHR

Abstract

Abstract-Both known estrogen receptors, ER␣ and ER␤, are expressed in blood vessels. To gain further insight into the role of ER␣ in a functional setting, we investigated the effect of the novel highly selective ER␣ agonist Cpd1471 on vascular reactivity in ovariectomized spontaneously hypertensive rats (SHR). After ovariectomy or sham operation, 12-week-old female SHR received either 17␤-estradiol (E2, 2 g/kg body wt per day), the selective ER␣ agonist Cpd1471 (30 g/kg body wt per day), or placebo. Acetylcholine-induced endothelium-dependent vasorelaxation was significantly blunted in aortas from ovariectomized rats (R max , 53%Ϯ3% versus sham, 79%Ϯ2%; PϽ0.001). Treatment with E2 or Cpd1471 significantly augmented acetylcholine-induced relaxation in ovariectomized rats (R max , 70%Ϯ2%; resp, 73%Ϯ2%). Endothelium-independent relaxation induced by sodium nitroprusside was not different among the four groups. The contractile response induced by the nitric oxide (NO) synthase inhibitor N-nitro-L-arginine, an index of basal NO formation, was significantly lower in ovariectomized rats compared with sham-operated animals (53Ϯ2% versus 77%Ϯ5%; PϽ0.01) and was normalized by both E2 (70%Ϯ2%) and Cpd1471 (70%Ϯ3%). Aortic endothelial NO synthase (eNOS) expression and phosphorylation of the vasodilator-stimulated phosphoprotein, an index of NO/cGMP-signaling, was reduced in ovariectomized SHR and normalized by E2 and Cpd1471. In SHR after ovariectomy, endothelium-dependent NO-mediated vasorelaxation and eNOS expression are attenuated. The novel selective ER␣ agonist Cpd1471 prevented these pathophysiological changes to a similar extent as E2. Thus, the pharmacological principle of selective ER␣ activation mediates positive vascular effects. Key Words: estrogen Ⅲ endothelium Ⅲ nitric oxide Ⅲ nitric oxide synthase Ⅲ rats, spontaneously hypertensive G ender differences in the risk for cardiovascular diseases are well recognized, with premenopausal women exhibiting a lower risk than age-matched men. The advantage of women over men in cardiovascular morbidity disappears after menopause, suggesting that estrogen plays an important role in cardiovascular health. 1 Estrogens are known to exert beneficial effects on the vascular wall. Long-term estrogen treatment improves endothelial dysfunction, a major contributor to the pathophysiology of cardiovascular disease, through upregulation of endothelial cell genes, such as endothelial nitric oxide synthase (eNOS). 2-4 Furthermore, estrogen has rapid nongenomic effects on the vascular endothelium, including activation of nitric oxide (NO) synthesis. 5,6 However, despite the positive effects on vascular function in animal models 7-9 and humans, 10 -14 estrogen replacement therapy with 17␤-estradiol or mixtures of equine estrogens as in the Heart and Estrogen/progestin Replacement Study (HERS) has failed to protect from cardiovascular diseases in large controlled clinical trials. [15][16][17][18] Therefore, in recent years, research has focused on selective estrogen receptor modulation as...

Aging Reduces the Efficacy of Estrogen Substitution to Attenuate Cardiac Hypertrophy in Female Spontaneously Hypertensive Rats

“…In line with previous observations, E2 efficiently attenuated cardiac hypertrophy in ovariectomized young SHRs, but blood pressure levels were not significantly different among all of the groups of young SHRs. 10,19 These findings indicate that estrogens are able to attenuate cardiac growth also by direct and blood pressure-independent mechanisms, such as cardiac ANP expression and mitogen-activated protein kinase activation, as we and others have reported before. 20 But in contrast to young animals, estrogen substitution failed to attenuate cardiac hypertrophy in aged SHRs.…”

Sex Steroids, Cardiovascular Disease, and Hypertension

“…21 In premenopausal women, a differential ratio of ET A to ET B receptors has also been found, favoring a vasodilator effect of endothelin via ET B receptors. 22 In recent animal studies, estradiol 23 or its metabolites 24 have been shown to inhibit endothelin synthesis and improve endothelial dysfunction in ovariectomized female spontaneously hypertensive rats 25 and DOCA-salt hypertensive rats. 23 Therefore, estrogens should be cardiovascular protective because of their positive effect on endothelin inhibition.…”

The Effects of Biological Sex and Diet on the Development of Heart Failure

“…The findings that cardiovascular risk increases when estrogen production ceases and that ovariectomy prevents the more beneficial outcome of volume overload or aging in females argues in favor of a protective role of estrogen. 3,4 In contrast, the finding that estradiol-treated female rodents have a greater post-MI rate of death argues against a protective role. 5,6 Recent human studies on hormone replacement therapy similarly question the cardioprotective role of estrogen.…”