Masaki Imanishi1, Shuhei Tomita2, Keisuke Ishizawa3, Yoshitaka Kihira1, Masaki Ueno4, Yuki Izawa-Ishizawa1, Yasumasa Ikeda1, Noriko Yamano1, Koichiro Tsuchiya3, Toshiaki Tamaki1. 1. Department of Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan. 2. 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. 3. Department of Medical Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, 1-78-1 Shoumachi, Tokushima 770-8505, Japan. 4. Department of Pathology and Host Defense, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
Abstract
AIM: 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. METHODS AND 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. CONCLUSION: Our results revealed that SMC-derived Hif-1α is a crucial mediator of Ang II-induced vascular remodelling. Published on behalf of the European Society of Cardiology. All rights reserved.
AIM: 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. METHODS AND 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. CONCLUSION: Our results revealed that SMC-derived Hif-1α is a crucial mediator of Ang II-induced vascular remodelling. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Steven J Forrester; George W Booz; Curt D Sigmund; Thomas M Coffman; Tatsuo Kawai; Victor Rizzo; Rosario Scalia; Satoru Eguchi Journal: Physiol Rev Date: 2018-07-01 Impact factor: 37.312
Authors: Nancy L Sehgel; Zhe Sun; Zhongkui Hong; William C Hunter; Michael A Hill; Dorothy E Vatner; Stephen F Vatner; Gerald A Meininger Journal: Hypertension Date: 2014-12-01 Impact factor: 10.190