Distinct role of estrogen receptor-alpha and beta on postmenopausal diabetes-induced vascular dysfunction

Abstract

Estrogen is known to influence vascular functions and insulin sensitivity, but the relative contribution of estrogen receptor (ER) isoforms in postmenopausal diabetes-induced vascular dysfunction is unclear. The aim of the present study was to delineate the distinct role of estrogen receptor-α and beta β on the vascular function in ovariectomized diabetic rats. Age matched 60 female sprague dawley rats (200–250g) were divided in nine groups. Bilateral ovariectomy was performed and streptozotocin was used to induce experimental diabetes. Rats were administered with 10μg/kg; s.c. of a nonselective estrogen receptor agonist, 17-β estradiol (E2), selective ER-α agonist (4,4′,4″-(4-propyl-[1H] pyrazole-1,3,5-triyl) tris phenol (PPT) and selective ER-β agonist, 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN) for 4weeks after STZ injection. Treatment with selective ER-α agonist and E2 improved the impaired glycemic and lipid profile in ovariectomized diabetic rats, however selective ER-β agonist did not show any effect. Vascular endothelial dysfunction was assessed by acetylcholine and sodium nitroprusside-induced endothelium dependent and independent relaxation in isolated rat aortic ring preparation as well as by electron microscopy of thoracic aorta. Further, serum thiobarbituric acid reactive substances, tumour necrotic factor-alpha and interleukin-1 beta and C-reactive protein were estimated to assess oxidative stress and vascular inflammation. Treatment with ER-α agonist markedly and E2 partially improved vascular function and endothelial integrity along with reduction in serum TBARS and inflammatory cytokines. However, ER-β agonist did not show any improvement in vascular functions, oxidative stress or inflammation. These findings suggest that selective targeting of ER-α receptors results in vasculoprotection in the state of hypoestrogenicity and diabetes.