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

Abstract

We investigated the role of angiotensin II type 1 (AT 1 ) and AT 2 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 AT 1 antagonist losartan (10 mg/kg per day PO), the AT 1 /AT 2 antagonist Sar 1 -Ile 8 -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, AT 1 blockade exerted antigrowth effects and reduced stiffness of small resistance arteries by decreasing nonelastic fibrillar components (collagen and fibronectin). Concomitant AT 1 /AT 2 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 AT 1 receptors that increase fibronectin and vascular stiffness and AT 2 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.