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

Abstract

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) Ϯ 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 g/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 (ϩ21%), which was partially decreased by losartan (Ϫ11%) and abrogated by Sar-Ile. Hydralazine markedly increased growth index (ϩ32%) 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 (PϽ0.05), 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. Key Words: collagen Ⅲ extracellular matrix Ⅲ renin-angiotensin system A ngiotensin II (Ang II), a potent vasoconstrictor of small resistance arteries, induces hypertrophy and hyperplasia of vascular smooth muscle cells (SMCs) mainly via Ang II type 1 (AT 1 ) receptors and has been implicated in the development and maintenance of hypertension. 1 Most of the biological effects of Ang II are mediated through AT 1 receptors. AT 2 receptor function is less well defined. Despite low AT 2 receptor expression in adult tissues, their abundance is increased after blood vessel injury 2 and can equal or exceed that of AT 1 in pathophysiological conditions. 3 The functional significance of AT 2 receptors remains uncertain. However, a recent study demonstrated that intrabrachial infusion of the AT 2 receptor antagonist PD123319 had significant systemic effects on mean arterial pressure during placebo and therapy with the AT 1 receptor antagonist telmisartan without affecting forearm blood flow, suggesting the presence of functionally effective AT 2 receptors. 4 Additionally, the AT 1 receptor antagonist candesartan unmasked the vasodilatory response to Ang II, suggesting that AT 2 rece...

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