This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Harada, K. Articles by Yazaki, Y. Search for Related Content PubMed PubMed Citation Articles by Harada, K. Articles by Yazaki, Y. Related Collections Cell signalling/signal transduction Genetically altered mice Other Vascular biology

(Circulation Research. 1999;84:179-185.)
© 1999 American Heart Association, Inc.

Original Contribution

Vascular Injury Causes Neointimal Formation in Angiotensin II Type 1a Receptor Knockout Mice

Koichiro Harada, Issei Komuro, Takeshi Sugaya, Kazuo Murakami, Yoshio Yazaki

From Department of Cardiovascular Medicine (K.H., I.K., Y.Y.), University of Tokyo Graduate School of Medicine, Tokyo; Lead Generation Research Laboratories (T.S.), Tanabe Seiyaku Co, Ltd, Osaka; and Institute of Applied Biochemistry (K.M.), University of Tsukuba, Ibaraki, Japan.

Correspondence to Issei Komuro, MD, PhD, Department of Cardiovascular Medicine, University of Tokyo, Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan. E-mail komuro-tky{at}umin.u-tokyo.ac.jp

Abstract—Many studies using small-animal models suggest that angiotensin II (Ang II) plays an important role in neointimal formation after vascular injury. In the present study, we examined whether Ang II type 1 receptor (AT₁)-mediated Ang II signaling is indispensable for the development of injury-induced neointimal formation using AT_1a knockout (KO) mice. Reverse transcriptase–polymerase chain reaction analysis revealed that AT₁ mRNA was not detectable in both uninjured and injured carotid arteries of KO mice, whereas the AT₁ gene was expressed in uninjured carotid arteries of wild-type (WT) mice. At 14 days after injury, AT₁ mRNA levels were increased by 1.5-fold in injured arteries of WT mice. Although AT₂ mRNA was not detectable in uninjured arteries, expression of AT₂ gene was induced in both animal groups at 2 weeks after injury. Vascular injury induced neointimal formation in KO mice as well as in WT mice. There were no significant differences between WT and KO mice in the extent of histological findings such as increased cross-sectional areas of the neointima and the media, the number of proliferating smooth muscle cells, and the amount of collagen and fibronectin. Treatment with subpressor doses of Ang II after injury enhanced the growth of neointima in WT mice but not in KO mice. Moreover, treatment with the selective AT₁ antagonist CV-11974 before injury significantly decreased the formation of neointima in only WT mice, whereas treatment with the selective AT₂ antagonist PD-123319 before injury had no effects in both animal groups. These results suggest that AT₁-mediated Ang II signaling is not essential for the development of neointimal formation, although it may modify it.

Key Words: angiotensin • angioplasty • stenosis • carotid artery

This article has been cited by other articles:

				Y. Numaguchi, M. Ishii, R. Kubota, Y. Morita, K. Yamamoto, T. Matsushita, K. Okumura, and T. Murohara Ablation of Angiotensin IV Receptor Attenuates Hypofibrinolysis via PAI-1 Downregulation and Reduces Occlusive Arterial Thrombosis Arterioscler Thromb Vasc Biol, December 1, 2009; 29(12): 2102 - 2108. [Abstract] [Full Text] [PDF]

				M. Takahashi, E. Suzuki, R. Takeda, S. Oba, H. Nishimatsu, K. Kimura, T. Nagano, R. Nagai, and Y. Hirata Angiotensin II and tumor necrosis factor-{alpha} synergistically promote monocyte chemoattractant protein-1 expression: roles of NF-{kappa}B, p38, and reactive oxygen species Am J Physiol Heart Circ Physiol, June 1, 2008; 294(6): H2879 - H2888. [Abstract] [Full Text] [PDF]

				H. Sano, K. Hosokawa, H. Kidoya, and N. Takakura Negative Regulation of VEGF-Induced Vascular Leakage by Blockade of Angiotensin II Type 1 Receptor Arterioscler Thromb Vasc Biol, December 1, 2006; 26(12): 2673 - 2680. [Abstract] [Full Text] [PDF]

				K. Yamamoto, T. Shioi, K. Uchiyama, T. Miyamoto, S. Sasayama, and A. Matsumori Attenuation of virus-induced myocardial injury by inhibition of the angiotensin II type 1 receptor signal and decreased nuclear factor-kappa B activation in knockout mice J. Am. Coll. Cardiol., December 3, 2003; 42(11): 2000 - 2006. [Abstract] [Full Text] [PDF]

				J. Suzuki, M. Iwai, H. Nakagami, L. Wu, R. Chen, T. Sugaya, M. Hamada, K. Hiwada, and M. Horiuchi Role of Angiotensin II-Regulated Apoptosis Through Distinct AT1 and AT2 Receptors in Neointimal Formation Circulation, August 13, 2002; 106(7): 847 - 853. [Abstract] [Full Text] [PDF]

				D. G. Kuhel, B. Zhu, D. P. Witte, and D. Y. Hui Distinction in Genetic Determinants for Injury-Induced Neointimal Hyperplasia and Diet-Induced Atherosclerosis in Inbred Mice Arterioscler Thromb Vasc Biol, June 1, 2002; 22(6): 955 - 960. [Abstract] [Full Text] [PDF]

				L. Wu, M. Iwai, H. Nakagami, Z. Li, R. Chen, J. Suzuki, M. Akishita, M. de Gasparo, and M. Horiuchi Roles of Angiotensin II Type 2 Receptor Stimulation Associated With Selective Angiotensin II Type 1 Receptor Blockade With Valsartan in the Improvement of Inflammation-Induced Vascular Injury Circulation, November 27, 2001; 104(22): 2716 - 2721. [Abstract] [Full Text] [PDF]

				D. Godin, E. Ivan, C. Johnson, R. Magid, and Z. S. Galis Remodeling of Carotid Artery Is Associated With Increased Expression of Matrix Metalloproteinases in Mouse Blood Flow Cessation Model Circulation, December 5, 2000; 102(23): 2861 - 2866. [Abstract] [Full Text] [PDF]