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 7

Decreased cell proliferation in the neointima of Rock1+/– mice.

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Decreased cell proliferation in the neointima of Rock1+/– mice. (A) ...
(A) Representative histological sections from carotid arteries in WT and Rock1+/– mice stained for PCNA at 14 days after ligation. Arrowheads indicate PCNA-positive cells. Scale bars: 50 μm (left panels). Quantitative analysis of the ratio of PCNA-positive cells to total cell number in the intima and the media (n = 10–16) (right panel). *P < 0.01 versus WT mice. (B) Cell proliferation in response to serum of VSMCs from WT and Rock1+/– mice. Experiments were performed 6 times in triplicates. (C) DNA synthesis in response to PDGF of VSMCs from WT and Rock1+/– mice (n = 12). *P < 0.01 versus without PDGF (control). (D) Cell migration in response to PDGF of VSMCs from WT and Rock1+/– mice (n = 8­–9). *P < 0.01 versus without PDGF (control); †P < 0.01 versus control; ΧP < 0.01 versus WT. (E) Representative western blot analysis of ROCK and ERK activities in VSMCs of WT and Rock1+/– mice. VSMCs were stimulated with 10 ng/ml of PDGF for the indicated time periods.