Angiotensin II AT1 receptors regulate ACE2 and angiotensin-(1-7) expression in the aorta of spontaneously hypertensive rats

Hypertension and Vascular Disease Center and Department of General Surgery, Wake Forest University School of Medicine, Winston-Salem, North Carolina Submitted 24 January 2005 ; accepted in final form 12 April 2005 When increased in vascular tissues, angiotensin-converting enzyme 2 (ACE2), a carboxypeptidase that hydrolyzes angiotensin II to angiotensin-(1–7), may augment the growth inhibitory and vasodilatory effects of the heptapeptide. We investigated the regulation of ACE2 and angiotensin-(1–7) expression in aortas and carotid arteries of 12-wk-old male spontaneously hypertensive rats (SHR) by determining the effect of sustained angiotensin type 1 (AT 1 ) receptor blockade with olmesartan (10 mg·kg –1 ·day –1 , n = 13) compared with those that received atenolol (30 mg·kg –1 ·day –1 , n = 13), hydralazine (10 mg·kg –1 ·day –1 , n = 13), or vehicle ( n = 21). Systolic blood pressures were 30% lower ( P < 0.05) in rats treated for 2 wk with olmesartan compared with vehicle-treated rats. Both atenolol and hydralazine produced similar decreases in systolic blood pressure. ACE2 mRNA in the thoracic aorta of olmesartan-treated rats ( n = 8) was fivefold greater ( P < 0.05) than that in vehicle-treated rats ( n = 16), whereas atenolol ( n = 8) or hydralazine ( n = 8) had no effect. Immunostaining intensities in rats treated with olmesartan ( n = 5) were also associated with increased ( P < 0.05) ACE2 and angiotensin-(1–7) in thoracic aorta media compared with vehicle-treated rats. In contrast, immunostaining intensities for both ACE2 and angiotensin-(1–7) were not different from vehicle ( n = 5) in carotid arteries of SHR medicated with either atenolol ( n = 5) or hydralazine ( n = 5). A comparison of vessel wall dimensions showed that olmesartan selectively reduced the thoracic aorta media-to-lumen ratio ( P < 0.05) and media thickness ( P < 0.05) without an effect on carotid artery morphometry. Compared with vehicle-treated SHR, vascular hypertrophy determined from media and lumen measurements was not changed in SHR given either atenolol or hydralazine. These data represent the first report of ACE2 and angiotensin-(1–7) expression in the aorta and carotid arteries of SHR. Increased ACE2 and angiotensin-(1–7) in association with altered dimensions of the thoracic aorta but not carotid arteries in response to olmesartan treatment provides evidence that this pathway is regulated by AT 1 receptors and may be important in mediating the pressure-independent vascula