Nature Medicine
- 12, 1075 - 1080 (2006)
Published online: 6 August 2006; | doi:10.1038/nm1459
Apoptosis of vascular smooth muscle cells induces features of plaque vulnerability in atherosclerosisMurray C H Clarke1, Nichola Figg1, Janet J Maguire2, Anthony P Davenport2, Martin Goddard3, Trevor D Littlewood1 & Martin R Bennett11
Division of Cardiovascular Medicine, University of Cambridge, Box 110, ACCI, Addenbrooke's Hospital, Cambridge, CB2 2QQ, UK. 2
Department of Clinical Pharmacology, University of Cambridge, Box 110, ACCI, Addenbrooke's Hospital, Cambridge, CB2 2QQ, UK. 3
Department of Pathology, Papworth Hospital, Cambridge, CB3 8RE, UK.
Correspondence should be addressed to Martin R Bennett mrb@mole.bio.cam.ac.uk Vascular smooth muscle cell (VSMC) apoptosis occurs in many arterial diseases, including aneurysm formation, angioplasty restenosis and atherosclerosis. Although VSMC apoptosis promotes vessel remodeling, coagulation and inflammation, its precise contribution to these diseases is unknown, given that apoptosis frequently accompanies vessel injury or alterations to flow. To study the direct consequences of VSMC apoptosis, we generated transgenic mice expressing the human diphtheria toxin receptor (hDTR, encoded by HBEGF) from a minimal Tagln (also known as SM22 ) promoter. Despite apoptosis inducing loss of 50–70% of VSMCs, normal arteries showed no inflammation, reactive proliferation, thrombosis, remodeling or aneurysm formation. In contrast, VSMC apoptosis in atherosclerotic plaques of SM22-hDTR Apoe-/- mice induced marked thinning of fibrous cap, loss of collagen and matrix, accumulation of cell debris and intense intimal inflammation. We conclude that VSMC apoptosis is 'silent' in normal arteries, which have a large capacity to withstand cell loss. In contrast, VSMC apoptosis alone is sufficient to induce features of plaque vulnerability in atherosclerosis. SM22-hDTR Apoe-/- mice may represent an important new model to test agents proposed to stabilize atherosclerotic plaques.
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