Molecular Medicine Reports 2015-11-01

Fasudil, a Rho‑kinase inhibitor, prevents intima‑media thickening in a partially ligated carotid artery mouse model: Effects of fasudil in flow‑induced vascular remodeling.

Xiangyu Zhang, Tao Zhang, Fu Gao, Qingle Li, Chenyang Shen, Yankui Li, Wei Li, Xiaoming Zhang

Index: Mol. Med. Report. 12 , 7317-25, (2015)

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Abstract

Vascular remodeling in response to hemodynamic alterations is a physiological process that requires coordinated signaling between endothelial, inflammatory and vascular smooth muscle cells (VSMCs). Extensive experimental and clinical studies have indicated the critical role of the Ras homolog gene family, member A/Rho‑associated kinase (ROCK) signaling pathway in the pathogenesis of cardiovascular disease, where ROCK activation has been demonstrated to promote inflammation and remodeling through inducing the expression of proinflammatory cytokines and adhesion molecules in endothelial cells and VSMCs. However, the role of ROCK in flow‑induced vascular remodeling has not been fully defined. The current study aimed to investigate the effect of the ROCK signaling pathway in flow‑induced vascular remodeling by comparing the responses to partial carotid artery ligation in mice treated with fasudil (a ROCK inhibitor) and untreated mice. Intima‑media thickness and neointima formation were evaluated by morphology. VSMC proliferation and inflammation of the vessel wall were assessed by immunohistochemistry. In addition, the expression levels of ROCK and the downstream effectors of ROCK, myosin light chain (MLC) and phosphorylated‑MLC (p‑MLC), were quantified by western blot analysis. Following a reduction in blood flow, ROCK1 and p‑MLC expression increased in the untreated left common carotid arteries (LCA). Fasudil‑treated mice developed a significantly smaller intima‑media thickness compared with the untreated mice. Quantitative immunohistochemistry of the fasudil‑treated LCA indicated that there was a reduction in proliferation when compared with untreated vessels. There were fewer CD45+ cells observed in the fasudil‑treated LCA compared with the untreated LCA. In conclusion, the expression of ROCK was enhanced in flow‑induced carotid artery remodeling and ROCK inhibition as a result of fasudil treatment may attenuate flow‑induced carotid artery remodeling.