Endothelial dysfunction and oxidative stress during estrogen deficiency inspontaneously hypertensive rats

Background-Postmenopausal estrogen deficiency is associated with an increas ed cardiovascular risk, hypertension, and oxidative stress. Angiotensin typ e 1 (AT(1)) receptor regulation is involved in the pathogenesis of atherosc lerosis, To characterize vascular function, oxidative stress, and AT(1) rec eptor regulation during estrogen deficiency, ovariectomized spontaneously h ypertensive rats (SHR) were investigated in comparison with sham-operated a nimals and with ovariectomized rats receiving estrogen replacement therapy with 17 beta -estradiol. Methods and Results-Arterial blood pressure was similar in all 3 groups inv estigated. Five weeks after ovariectomy, endothelial dysfunction in aortic rings was observed, which was reversed by estrogen replacement therapy. Est rogen deficiency led to an enhanced vasoconstriction by angiotensin II. Vas cular superoxide production was significantly increased compared with that in sham-operated rats, as measured by lucigenin chemiluminescence assays. E strogen substitution normalized the production of free radicals in the vess el wall. Vascular AT(1) receptor expression was significantly upregulated b y estrogen deficiency, as shown by quantitative reverse transcription-polym erase chain reaction, whereas endothelial NO synthase mRNA expression and N O release were unchanged. Five-week treatment of the animals with the AT(1) receptor antagonist irbesartan prevented endothelial dysfunction in ovarie ctomized rats and normalized the vascular production of free radicals. Conclusions-In SHR, estrogen deficiency leads to increased vascular free ra dical production and enhanced angiotensin II-induced vasoconstriction via i ncreased vascular AT(1) receptor expression, resulting in endothelial dysfu nction. Estrogen replacement therapy and AT(1) receptor antagonism prevent these pathological changes. Therefore, estrogen deficiency-induced AT(1) re ceptor overexpression and oxidative stress may play an important role in ca rdiovascular diseases associated with menopause.