Abstract 11903: Hypoxia-inducible Factor-1α in Vascular Smooth Muscle Cells Regulates Angiotensin II-induced Vascular Remodeling and AT1 Receptor Expression in Mouse Aortic Media
HIF-1α is induced by angiotensin II (Ang II), cytokines and growth factors, in addition to hypoxic condition. Recently, several studies have suggested that HIF-1α up-regulation links to cell proliferation and resistance to apoptosis in vascular smooth muscle cells (VSMCs). Migration and proliferation of VSMCs induce vascular remodeling leading to the medial hyperplasia. To clarify the role of HIF-1α in the development of vascular remodeling, we created smooth muscle cell-specific HIF-1α-deficient mice (SMKO). Ang II infusion (2.5 mg/kg/day, 4 weeks, n=10) by mini-osmotic pump increased HIF-1α mRNA and protein expression in aorta of control mice (CONT), but not of SMKO (p=0.0001, 0.0001). Ang II increased medial thickness, fibrosis area around the aorta, the number of Ki67 positive cells in the medial area and superoxide production in aortic wall in CONT, but not in SMKO (ratio of medial area to luminal area; CONT with Ang II vs SMKO with Ang II; 0.53±0.02 vs 0.45±0.02, p=0.0212). To investigate how HIF-1α contributes to oxidative stress in aortic wall in this model, we evaluated AT1 receptor (AT1) expression in aorta. Its mRNA and protein expressions were induced by Ang II in CONT, but not in SMKO (p=0.0001, 0.0003). AT1 immunostaining of the aorta sections also showed AT1 induction by Ang II of the medial area in CONT was reduced in SMKO. The levels of mRNA expressions of plasminogen activator inhibitor-1 (PAI-1), collagen I, IL-1β and monocyte chemotactic protein-1 in aorta were also elevated by Ang II in CONT, but not in SMKO (p=0.0071, 0.0058, 0.0299, 0.0220). SMC-specific HIF-1α deficiency did not affect mRNA expressions of NADPH oxidase components except for p22phox in aorta. In our in vitro studies, Ang II elevated cell migration activity of VSMCs, but this effect was canceled by HIF-1α knockdown (1.55±0.06 vs 1.06±0.04 fold increase, p=0.0001). Dimethyloxallyl glycine, HIF-1α prolyl hydroxylase inhibitor which induces HIF-1α, induced mRNA expressions of AT1, PAI-1 and collagen I, but these effects were also canceled by HIF-1α knockdown. These findings suggest that HIF-1α regulates AT1 expression and contributes to development of vascular remodeling via those downstream pathways in VSMCs.
- © 2012 by American Heart Association, Inc.