Angiotensin-(1–7) Reduces Smooth Muscle Growth After Vascular Injury

Abstract

Abstract-Regulation of vascular smooth muscle cell growth is critical to the maintenance of normal blood flow and vessel patency. Angiotensin-(1-7) [Ang-(1-7)] inhibits proliferation of vascular smooth muscle cells in vitro and opposes the mitogenic effects of angiotensin II. The present study investigated whether Ang-(1-7) inhibits vascular smooth muscle cell growth in vivo by determining its effect on neointimal formation and medial remodeling in balloon-injured carotid arteries. The carotid arteries of adult male Sprague-Dawley rats were injured with a balloon embolectomy catheter. Ang-(1-7) in saline (24 g/kg per hour) or saline alone was infused intravenously for 12 days after injury. Pumps containing bromodeoxyuridine were implanted at the same time to determine DNA synthesis. Intravenous infusion increased plasma Ang-(1-7) to 166.0Ϯ41.2 fmol/mL (nϭ6) compared with 46.9Ϯ4.2 fmol/mL (nϭ8) in saline-infused rats. Plasma concentrations of Ang II were not changed by Ang-(1-7) infusion. Elevation in circulating Ang-(1-7) had no effect on either blood pressure or heart rate compared with saline controls. Histomorphometric analysis of carotid arteries indicated that Ang-(1-7) infusion significantly reduced neointimal area compared with rats infused with saline (0.063Ϯ0.011 versus 0.100Ϯ0.009 mm 2 ; PϽ0.05). In contrast, Ang-(1-7) infusion had no effect on medial area of the injured or the contralateral uninjured artery compared with saline controls. Ang-(1-7) infusion also reduced the rate of DNA synthesis in both the neointima and the media of the injured vessels. Therefore, exogenous Ang-(1-7) inhibited vascular smooth muscle cell proliferation associated with balloon-catheter injury. Similar increases in endogenous plasma Ang-(1-7) and inhibition of neointimal growth were observed in rats after angiotensin-converting enzyme inhibitor or angiotensin type 1 receptor antagonist administration, suggesting that Ang-(1-7) may contribute to the in vivo antiproliferative effects of these agents on vascular smooth muscle.

Angiotensin‐(1‐7): Pharmacology and New Perspectives in Cardiovascular Treatments

“…In a follow-up study from our group, Ang-(1-7) administered continuously for 12 days after carotid artery balloon catheter injury inhibited neointimal formation compared to saline-infused control rats (Strawn et al 1999). Elevated endogenous Ang-(1-7) by ACE inhibition or angiotensin receptor blockade also yielded similar results.…”

“…It is well documented that Ang II promotes cell proliferation (Daemen et al 1991;Su et al 1998) and vasoconstriction (Wackenfors et al 2004), whereas Ang-(1-7) has antiproliferative actions on cardiac myocytes (Tallant et al 2005) and vascular smooth muscle (Strawn et al 1999), and is a vasodilator . These actions have uncovered a new way to think about the RAS, both conceptually and therapeutically.…”

Hemodynamic effects of vasorelaxant compounds in mice lacking one, two or all three angiotensin II receptors

“…7 In addition to its vascular effects, it was shown that Ang-(1-7) also has beneficial effects on cardiac function. [9][10][11] Moreover, it opposes the growth-stimulating effects of Ang II in vascular smooth muscle cells 12 and cardiomyocytes. 13 Ang-(1-7) also demonstrates effects on renal function by participating in the control of water and electrolyte homeostasis.…”

Chymase-dependent angiotensin II formation in human blood vessels

“…It has been shown that angiotensin [1][2][3][4][5][6][7] possesses the ability to stimulate the release of vasodilator prostanoids and nitric oxide, as well as inhibiting proliferation of vascular smooth muscle cells in balloon injured carotid arteries and rat aorta. [29][30][31] Angiotensin II may also be generated via the action of tonin. Tonin, a kallikrenin-like protease has the ability to form angiotensin II from angiotensin I as well as directly from the synthetic renin substrate and from human angiotensinogen.…”