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 SM22α) 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 SM22α-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. SM22α-hDTR Apoe−/− mice may represent an important new model to test agents proposed to stabilize atherosclerotic plaques.
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This study was supported by British Heart Foundation Grants PG/02/055/13778 and RG 04/001 (to M.R.B.); PG/05/127/19872 and PS/02/001 (to A.P.D.) and the European Vascular Genomics Network of Excellence (FP6).
The authors declare no competing financial interests.
Generation and characterization of transgenic mice. (PDF 133 kb)
Genotyping of Tgln2-HBEGF and Tgln2-HBEGF Apoe−/− mice. (PDF 901 kb)
Administration of DT induces VSMC-specific apoptosis in Tgln2-HBEGF mice. (PDF 92 kb)
Administration of DT does not induce nonspecific SMC loss in SM22α-hDTR mice. (PDF 170 kb)
VSMC apoptosis does not induce lymphocyte infiltration or expression of MCP-1/JE. (PDF 149 kb)
VSMC apoptosis induces vulnerable plaques in brachiocephalic arteries. (PDF 152 kb)
VSMC apoptosis increases serum IL-6. (PDF 82 kb)
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