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(Hypertension. 2005;46:598.)
© 2005 American Heart Association, Inc.

Original Articles

Combined Angiotensin II Type 1 and Type 2 Receptor Blockade on Vascular Remodeling and Matrix Metalloproteinases in Resistance Arteries

From the Canadian Institutes of Health Research, Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal, Quebec, Canada.

Correspondence to Ernesto L. Schiffrin, MD, PhD, FRCPC, Clinical Research Institute of Montreal, 110 Pine Ave W, Montreal, Quebec, Canada H2W 1R7. E-mail ernesto.schiffrin{at}ircm.qc.ca

We investigated the role of angiotensin II type 1 (AT₁) and AT₂ receptors, matrix metalloproteinases (MMPs), and extracellular matrix (ECM) components involved in vascular remodeling of resistance arteries induced by angiotensin II (Ang II). Sprague-Dawley rats received Ang II (120 ng/kg per minute SC) ± the AT₁ antagonist losartan (10 mg/kg per day PO), the AT₁/AT₂ antagonist Sar¹-Ile⁸-Ang II (Sar-Ile; 10 µg/kg per minute SC), or hydralazine (25 mg/kg per day PO) for 7 days. Structure and mechanical properties of small mesenteric arteries were evaluated on a pressurized myograph. Ang II increased growth index (+21%), which was partially decreased by losartan (–11%) and abrogated by Sar-Ile. Hydralazine markedly increased growth index (+32%) despite systolic blood pressure (BP) lowering, suggesting a BP-independent effect of Ang II on vascular growth. Elastic modulus was increased by Sar-Ile compared with Ang II and control. Vascular type I collagen was reduced (P<0.05), whereas fibronectin increased significantly with Sar-Ile. Vascular tissue inhibitor of metalloproteinase-2 binding to MMP-2 was abrogated by Sar-Ile, but MMP-2 activity was significantly increased compared with losartan, Ang II, and controls. Thus, AT₁ blockade exerted antigrowth effects and reduced stiffness of small resistance arteries by decreasing nonelastic fibrillar components (collagen and fibronectin). Concomitant AT₁/AT₂ blockade prevented growth, reduced collagen type I and elastin deposition but increased vascular stiffness, fibronectin, and MMP-2 activity. These results demonstrate opposing roles of AT₁ receptors that increase fibronectin and vascular stiffness and AT₂ receptors that decrease MMP-2 and increase elastin. Changes in vascular wall mechanics, ECM deposition, and MMP activity are thus modulated differentially by Ang II receptors.

Key Words: collagen • extracellular matrix • renin-angiotensin system

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