title: Smooth muscle cell-specific Hif-1α deficiency suppresses angiotensin II-induced vascular remodelling in mice.
abstract: OBJECTIVE
  Vascular remodelling is mediated by vascular smooth muscle cell (VSMC) proliferation and hypertrophy, both processes of which are linked to medial thickening and fibrosis. Here, we show that hypoxia-inducible factor-1α (Hif-1α) expressed in smooth muscle cells (SMCs) is involved in angiotensin II (Ang II)-induced vascular remodelling in an in vivo model.
  
  
  RESULTS
  To clarify the role of Hif-1α in vascular remodelling, we created mice lacking the Hif-1α gene in SMCs (SMKO mice). Ang II infusion induced medial thickening and vascular fibrosis, accompanied by Hif-1α up-regulation, in the aortae of control mice, but not in those of SMKO mice. In accordance with those results, our in vitro studies showed that the deletion of SMC-derived Hif-1α suppressed the Ang II-induced hypertrophy of VSMCs, and our in vivo studies showed that the Ang II-induced expression of fibrosis-related genes in aortae was suppressed by SMC-specific Hif-1α deficiency. In addition, the SMC-specific Hif-1α deficiency suppressed Ang II-induced macrophage infiltration and Ang II-induced expression of inflammation-related genes in aortae. The superoxide production observed in the aortae of control mice with Ang II was suppressed in those of SMKO mice with Ang II, and this finding was consistent with the results of little Ang II-induced c-Src phosphorylation in SMKO mouse aortae. Loss- and gain-of-function analysis in in vitro experiments confirmed that VSMC-derived Hif-1α functions as an intrinsic modulator of vascular remodelling-related gene expression.
  
  
  CONCLUSIONS
  Our results revealed that SMC-derived Hif-1α is a crucial mediator of Ang II-induced vascular remodelling.
authors.affiliation: Department of Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Imanishi
authors.affiliation: Department of Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan Division of Molecular Pharmacology, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago-shi, Tottori 683-8503, Japan tomita@med.tottori-u.ac.jp.
authors.forename: Shuhei
authors.initials: S
authors.lastname: Tomita
authors.affiliation: Department of Medical Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, 1-78-1 Shoumachi, Tokushima 770-8505, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Ishizawa
authors.affiliation: Department of Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Kihira
authors.affiliation: Department of Pathology and Host Defense, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Ueno
authors.affiliation: Department of Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Izawa-Ishizawa
authors.affiliation: Department of Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Ikeda
authors.affiliation: Department of Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Yamano
authors.affiliation: Department of Medical Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, 1-78-1 Shoumachi, Tokushima 770-8505, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Tsuchiya
authors.affiliation: Department of Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Tamaki
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D005355:Fibrosis; D005786:Gene Expression Regulation; D006439:Hemodynamics; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000172:deficiency / Q000502:physiology*; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000473:pathology*; D032389:Myocytes, Smooth Muscle / Q000473:pathology*; D010766:Phosphorylation; D013481:Superoxides / Q000378:metabolism; D066253:Vascular Remodeling
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D013481:Superoxides; D000804:Angiotensin II
keywords: Angiotensin II; Hypoxia-inducible factor-1 (HIF-1); Vascular remodelling; Vascular smooth muscle