Abstract 11568: Smooth Muscle Cell-Specific Hypoxia-Inducible Factor-1α Deficiency Attenuates Angiotensin II-Induced Vascular Remodeling in Mice
Vascular remodeling leading to the medial hyperplasia is formed by migration and proliferation of vascular smooth muscle cells (VSMCs). Recently, several studies have suggested that HIF-1α up-regulation links to cell proliferation and resistance to apoptosis in VSMCs. HIF-1α is induced by angiotensin II (Ang II) and growth factors, in addition to hypoxic condition. To clarify the role of HIF-1α in the development of vascular remodeling, we created smooth muscle cell-specific HIF-1α-deficient (SMKO) mice. Ang II infusion (2.5 mg/kg/day, 4 weeks, n=8-10) by mini-osmotic pump increased mRNA expression levels of HIF-1α and HIF-1β in the aorta of control mice (p=0.0001, 0.0090), but not of SMKO mice. Ang II increased medial thickness and the number of Ki67 positive cells in the medial area in control mice, whereas no effects in SMKO mice (ratio of medial area to luminal area; control mice with Ang II vs SMKO mice with Ang II; 0.53± 0.02 vs 0.45± 0.02, p=0.0212). Fibrosis area around the aorta was also increased by Ang II in control mice, but not in SMKO mice. Systolic blood pressure (SBP) in SMKO mice with Ang II did not reach to that in control mice with Ang II (159± 5 vs 134± 4 (mmHg), p=0.0002). Additionally, changes in urinary excretion of albumin correlated with those in SBP (p=0.0094). The levels of mRNA expressions of plasminogen activator inhibitor-1, collagen I, IL-1β, monocyte chemotactic protein-1, F4/80 and CD68 in the aorta were also elevated by Ang II in control mice, but not in SMKO mice (p=0.0071, 0.0058, 0.0299, 0.0220, 0.0295, 0.0001). Superoxide production in the aortic wall was not increased by AngII in SMKO mice, whereas it was increased in control mice. The levels of mRNA expressions of p22phox, AT1A receptor and AT2 receptor were elevated by Ang II in control mice, but not in SMKO mice (p=0.0497, 0.0288, 0.0362). AT1A receptor immunostaining of the aorta sections showed AT1A receptor induction by Ang II of the medial area in control mice was reduced in SMKO mice. In addition, Ang II elevated cell migration activity of VSMCs, but that effect was canceled by HIF-1α knockdown using siRNA in vitro (1.55± 0.06 vs 1.06± 0.04 fold increase, p=0.0001). These findings suggest that HIF-1α in VSMCs plays key roles in Ang II-induced vascular remodeling.
- © 2011 by American Heart Association, Inc.