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(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

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