In rats, AT1 blockade with losartan decreased Ang II-induced vascular growth (-11%), while combined AT1/AT2 blockade abrogated growth but increased vascular stiffness and MMP-2 activity.
Does combined AT1 and AT2 receptor blockade alter vascular remodeling and matrix metalloproteinases in resistance arteries induced by Angiotensin II in Sprague-Dawley rats?
AT1 and AT2 receptors exert opposing roles in vascular remodeling, where AT1 blockade reduces stiffness and AT2 blockade decreases MMP-2 and increases elastin.
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 microg/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.
Brassard et al. (Tue,) conducted a other in Vascular remodeling. Losartan, Sar1-Ile8-Ang II, or hydralazine vs. Ang II alone and controls was evaluated on Growth index and vascular stiffness. In rats, AT1 blockade with losartan decreased Ang II-induced vascular growth (-11%), while combined AT1/AT2 blockade abrogated growth but increased vascular stiffness and MMP-2 activity.