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(Circulation Research. 2006;98:412.)
© 2006 American Heart Association, Inc.

Integrative Physiology

Accelerated Arteriosclerosis of Vein Grafts in Inducible NO Synthase^–/– Mice Is Related to Decreased Endothelial Progenitor Cell Repair

Ursula Mayr, Yiping Zou, Zhongyi Zhang, Hermann Dietrich, Yanhua Hu, Qingbo Xu

From the Department of Cardiac and Vascular Sciences (U.M., Z.Z., Y.H., Q.X.), St George’s University of London, London, United Kingdom; and Institute for Pathophysiology (Y.Z., H.D.), Innsbruck Medical University, Austria.

Correspondence to Qingbo Xu, MD, PhD, Department of Cardiac and Vascular Sciences, St George’s University of London, Cranmer Terrace, London SW17 0RE, United Kingdom. E-mail q.xu{at}sghms.ac.uk

Inducible NO synthase (iNOS) is expressed by macrophages and smooth muscle cells in atherosclerotic lesions. Previously, we have established a mouse model for vein graft arteriosclerosis by grafting autologous jugular veins or vena cava to carotid arteries. Using this model, we studied the role of iNOS in the development of vein graft arteriosclerosis in iNOS^–/– mice. Four weeks after grafting, neointimal hyperplasia of vein grafts in iNOS^–/– mice was increased 2-fold compared with that of wild-type controls. Neointimal lesions contained mainly MAC-1⁺ macrophages and -actin⁺ smooth muscle cells (SMCs) in both vein grafts of iNOS^–/– and iNOS^+/+ mice. Immunofluorescence analysis revealed that increased iNOS expression in neointimal macrophages and SMCs of wild-type, but not iNOS^–/–, mice coincided with increased vascular endothelial growth factor (VEGF) expression in vein grafts. When vein grafts were performed in iNOS^–/–/TIE2-LacZ transgenic mice expressing LacZ gene only in endothelial cells, the number of ß-galactosidase⁺ cells in iNOS^–/– vein grafts were significantly decreased. Furthermore, treatment with the NOS inhibitor N^G-nitro-L-arginine methyl ester resulted in delayed endothelial progenitor cell attachment, whereas L-arginine intake through drinking water enhanced endothelial repair. Interestingly, local application of VEGF to iNOS^–/– vein grafts restored endothelial progenitor homing and reduced neointimal lesions, whereas the VEGF receptor inhibitor SU1498 increased the lesion formation. Additionally, iNOS-deficient SMCs showed a low level of VEGF production in response to interleukin 1ß stimulation. Thus, iNOS deficiency accelerates neointima formation by abrogating VEGF production and endothelial progenitor cell attachment and differentiation.

Key Words: mouse models • iNOS • vein grafts • progenitor cells • neointimal hyperplasia

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