Accelerated arteriosclerosis of vein grafts in inducible NO synthase(-/-) mice is related to decreased endothelial progenitor cell repair.
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 alpha-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 beta-galactosidase+ cells in iNOS(-/-) vein grafts were significantly decreased. Furthermore, treatment with the NOS inhibitor NG-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 1beta stimulation. Thus, iNOS deficiency accelerates neointima formation by abrogating VEGF production and endothelial progenitor cell attachment and differentiation.
Mayr
Ursula
U
Department of Cardiac and Vascular Sciences, St George's University of London, London SW17 0RE, United Kingdom.
Zou
Yiping
Y
Zhang
Zhongyi
Z
Dietrich
Hermann
H
Hu
Yanhua
Y
Xu
Qingbo
Q
D000818:Animals; D001161:Arteriosclerosis / Q000453:epidemiology*; D001483:Base Sequence; D017931:DNA Primers; D004730:Endothelium, Vascular / Q000473:pathology*; D005838:Genotype; D051379:Mice; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D016133:Polymerase Chain Reaction; D013234:Stem Cells / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000502:physiology; D014684:Venae Cavae / Q000637:transplantation*
D017931:DNA Primers; D042461:Vascular Endothelial Growth Factor A; D052247:Nitric Oxide Synthase Type II