ROCK1 mediates leukocyte recruitment and neointima formation following vascular injury
Kensuke Noma, Yoshiyuki Rikitake, Naotsugu Oyama, Guijun Yan, Pilar Alcaide, Ping-Yen Liu, Hongwei Wang, Daniela Ahl, Naoki Sawada, Ryuji Okamoto, Yukio Hiroi, Koichi Shimizu, Francis W. Luscinskas, Jianxin Sun, James K. Liao
Kensuke Noma, Yoshiyuki Rikitake, Naotsugu Oyama, Guijun Yan, Pilar Alcaide, Ping-Yen Liu, Hongwei Wang, Daniela Ahl, Naoki Sawada, Ryuji Okamoto, Yukio Hiroi, Koichi Shimizu, Francis W. Luscinskas, Jianxin Sun, James K. Liao
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Research Article Cardiology

ROCK1 mediates leukocyte recruitment and neointima formation following vascular injury

Abstract

Although Rho-associated kinase (ROCK) activity has been implicated in cardiovascular diseases, the tissue- and isoform-specific roles of ROCKs in the vascular response to injury are not known. To address the role of ROCKs in this process, we generated haploinsufficient Rock1 (Rock1+/–) and Rock2 (Rock2+/–) mice and performed carotid artery ligations. Following this intervention, we found reduced neointima formation in Rock1+/– mice compared with that of WT or Rock2+/– mice. This correlated with decreased vascular smooth muscle cell proliferation and survival, decreased levels proinflammatory adhesion molecule expression, and reduced leukocyte infiltration. In addition, thioglycollate-induced peritoneal leukocyte recruitment and accumulation were substantially reduced in Rock1+/– mice compared with those of WT and Rock2+/– mice. To determine the role of leukocyte-derived ROCK1 in neointima formation, we performed reciprocal bone marrow transplantation (BMT) in WT and Rock1+/– mice. Rock1+/– to WT BMT led to reduced neointima formation and leukocyte infiltration following carotid ligation compared with those of WT to WT BMT. In contrast, WT to Rock1+/– BMT resulted in increased neointima formation. These findings indicate that ROCK1 in BM-derived cells mediates neointima formation following vascular injury and suggest that ROCK1 may represent a promising therapeutic target in vascular inflammatory diseases.

Authors

Kensuke Noma, Yoshiyuki Rikitake, Naotsugu Oyama, Guijun Yan, Pilar Alcaide, Ping-Yen Liu, Hongwei Wang, Daniela Ahl, Naoki Sawada, Ryuji Okamoto, Yukio Hiroi, Koichi Shimizu, Francis W. Luscinskas, Jianxin Sun, James K. Liao

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Figure 1

Decreased neointima formation after carotid artery ligation in Rock1+/– mice.

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Decreased neointima formation after carotid artery ligation in Rock1+/– ...
(A) Representative cross sections of contralateral unligated and ligated carotid arteries in WT, Rock1+/–, and Rock2+/– mice at 28 days after ligation. Scale bar: 100 μm. (B) Representative immunohistochemical analysis of ROCK expression and activity in carotid arteries from WT and Rock1+/– mice at 14 days after ligation. Vessels were stained with nonspecific antibody (IgG), and antibodies were directed at total MBS (tMBS), phosphorylated MBS (pMBS), ROCK1, and ROCK2. The I and M indicate the intima and media, respectively. Scale bar: 50 μm.