Apoptosis of vascular smooth muscle cells induces features of plaque vulnerability in atherosclerosis.
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 SM22alpha) 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 SM22alpha-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. SM22alpha-hDTR Apoe-/- mice may represent an important new model to test agents proposed to stabilize atherosclerotic plaques.
Clarke
Murray C H
MC
Division of Cardiovascular Medicine, University of Cambridge, Box 110, ACCI, Addenbrooke's Hospital, Cambridge, CB2 2QQ, UK.
Figg
Nichola
N
Maguire
Janet J
JJ
Davenport
Anthony P
AP
Goddard
Martin
M
Littlewood
Trevor D
TD
Bennett
Martin R
MR
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D017209:Apoptosis / Q000502:physiology*; D050197:Atherosclerosis / Q000473:pathology*; D016207:Cytokines / Q000097:blood; D004167:Diphtheria Toxin / Q000378:metabolism; D004195:Disease Models, Animal; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000235:genetics; D009124:Muscle Proteins / Q000235:genetics; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000473:pathology; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism
D001057:Apolipoproteins E; D016207:Cytokines; D004167:Diphtheria Toxin; C587883:HBEGF protein, human; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D008840:Microfilament Proteins; D009124:Muscle Proteins; D011956:Receptors, Cell Surface; C058992:Tagln protein, mouse