Published online before print October 11, 2004, doi: 10.1161/01.CIR.0000145138.25577.F1
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(Circulation. 2004;110:2436-2443.)
© 2004 American Heart Association, Inc.
Molecular Cardiology |
Angiogenesis-Dependent and Independent Phases of Intimal Hyperplasia
From the Centre for Cardiovascular Biology and Medicine (R.K., J.M., I.Z.), Department of Medicine, University College, London, UK; the Section of Cardiology (R.K., Z.Z., M.M., E.D.M., M.S.), Departments of Medicine and of Pharmacology and Toxicology, Dartmouth Medical School, Lebanon, NH; the Department of Biotechnology and Molecular Medicine (S.B., S.Y.-H.), A.I. Virtanen Institute for Molecular Sciences, University of Kuopio, Kuopio, Finland; and the Department of Molecular Oncology (N.F.), Genentech, Inc, South San Francisco, Calif.
Correspondence to Michael Simons, MD, Section of Cardiology, Dartmouth Hitchcock Medical Center, One Medical Center Dr, Lebanon, NH 03756. E-mail Michael.Simons{at}Dartmouth.edu
Received April 29, 2004; revision received June 11, 2004; accepted July 12, 2004.
Background— Neointimal vascular smooth muscle cell (VSMC) proliferation is a primary cause of occlusive vascular disease, including atherosclerosis, restenosis after percutaneous interventions, and bypass graft stenosis. Angiogenesis is implicated in the progression of early atheromatous lesions in animal models, but its role in neointimal VSMC proliferation is undefined. Because percutaneous coronary interventions result in induction of periadventitial angiogenesis, we analyzed the role of this process in neointima formation.
Methods and Results— Local injury to the arterial wall in 2 different animal models induced periadventitial angiogenesis and neointima formation. Application of angiogenesis stimulators vascular endothelial growth factor (VEGF-A165) or a proline/arginine-rich peptide (PR39) to the adventitia of the injured artery induced a marked increase in neointimal thickening beyond that seen with injury alone in both in vivo models. Inhibition of either VEGF (with soluble VEGF receptor 1 [sFlt1]) or fibroblast growth factor (FGF) (with a dominant=negative form of FGF receptor 1 [FGF-R1DN]), respectively, signaling reduced adventitial thickening induced by VEGF and PR39 to the level seen with mechanical arterial injury alone. However, neither inhibitor was effective in preventing neointimal thickening after mechanical injury when administered in the absence of angiogenic growth factor.
Conclusions— Our findings indicate that adventitial angiogenesis stimulates intimal thickening but does not initiate it.
Key Words: growth substances • restenosis • gene therapy
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