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Am J Physiol Cell Physiol 297: C1466-C1476, 2009. First published October 14, 2009; doi:10.1152/ajpcell.00304.2009
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Vascular Biology

Homocysteine promotes vascular smooth muscle cell migration by induction of the adipokine resistin

Changtao Jiang,1 Heng Zhang,1 Weizhen Zhang,1 Wei Kong,1 Yi Zhu,1 Hongquan Zhang,2 Qingbo Xu,5 Yin Li,1 and Xian Wang1,3,4

1Department of Physiology and Pathophysiology and 2Department of Anatomy and Histology Embryology, School of Basic Medical Sciences, Peking University, 3Institute of Vascular Medicine, Peking University Third Hospital, and 4Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, People's Republic of China; and 5Cardiovascular Division, King's College London British Heart Foundation Centre, London, United Kingdom

Submitted 13 July 2009 ; accepted in final form 14 September 2009

Adipokines may represent a mechanism linking insulin resistance to cardiovascular disease. We showed previously that homocysteine (Hcy), an independent risk factor for cardiovascular disease, can induce the expression and secretion of resistin, a novel adipokine, in vivo and in vitro. Since vascular smooth muscle cell (VSMC) migration is a key event in vascular disease, we hypothesized that adipocyte-derived resistin is involved in Hcy-induced VSMC migration. To confirm our hypothesis, Sprague-Dawley rat aortic SMCs were cocultured with Hcy-stimulated primary rat epididymal adipocytes or treated directly with increasing concentrations of resistin for up to 24 h. Migration of VSMCs was investigated. Cytoskeletal structure and cytoskeleton-related proteins were also detected. The results showed that Hcy (300–500 µM) increased migration significantly in VSMCs cocultured with adipocytes but not in VSMC cultured alone. Resistin alone also significantly increased VSMC migration in a time- and concentration-dependent manner. Resistin small interfering RNA (siRNA) significantly attenuated VSMC migration in the coculture system, which indicated that adipocyte-derived resistin mediates Hcy-induced VSMC migration. On cell spreading assay, resistin induced the formation of focal adhesions near the plasma membrane, which suggests cytoskeletal rearrangement via an {alpha}5β1-integrin-focal adhesion kinase/paxillin-Ras-related C3 botulinum toxin substrate 1 (Rac1) pathway. Our data demonstrate that Hcy promotes VSMC migration through a paracrine or endocrine effect of adipocyte-derived resistin, which provides further evidence of the adipose-vascular interaction in metabolic disorders. The migratory action exerted by resistin on VSMCs may account in part for the increased incidence of restenosis in diabetic patients.

adipose-vascular interaction; insulin resistance; cytoskeleton


Address for reprint requests and other correspondence: X. Wang and Y. Li, Dept. of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking Univ., Beijing 100191, People's Republic of China (e-mail: xwang{at}bjmu.edu.cn, yinli{at}bjmu.edu.cn).






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