Combined angiotensin II type 1 and type 2 receptor blockade on vascular remodeling and matrix metalloproteinases in resistance arteries

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 mu 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 ( + 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.