title: Chronic apoptosis of vascular smooth muscle cells accelerates atherosclerosis and promotes calcification and medial degeneration.
abstract: Vascular smooth muscle cell (VSMC) accumulation is implicated in plaque development. In contrast, VSMC apoptosis is implicated in plaque rupture, coagulation, vessel remodeling, medial atrophy, aneurysm formation, and calcification. Although VSMC apoptosis accompanies multiple pathologies, there is little proof of direct causality, particularly with the low levels of VSMC apoptosis seen in vivo. Using a mouse model of inducible VSMC-specific apoptosis, we demonstrate that low-level VSMC apoptosis during either atherogenesis or within established plaques of apolipoprotein (Apo)E(-/-) mice accelerates plaque growth by two-fold, associated with features of plaque vulnerability including a thin fibrous cap and expanded necrotic core. Chronic VSMC apoptosis induced development of calcified plaques in younger animals and promoted calcification within established plaques. In addition, VSMC apoptosis induced medial expansion, associated with increased elastic lamina breaks, and abnormal matrix deposition reminiscent of cystic medial necrosis in humans. VSMC apoptosis prevented outward remodeling associated with atherosclerosis resulting in marked vessel stenosis. We conclude that VSMC apoptosis is sufficient to accelerate atherosclerosis, promote plaque calcification and medial degeneration, prevent expansive remodeling, and promote stenosis in atherosclerosis.
authors.affiliation: University of Cambridge, Division of Cardiovascular Medicine, Addenbrooke's Hospital, Cambridge, United Kingdom.
authors.forename: Murray C H
authors.initials: MC
authors.lastname: Clarke
authors.forename: Trevor D
authors.initials: TD
authors.lastname: Littlewood
authors.forename: Nichola
authors.initials: N
authors.lastname: Figg
authors.forename: Janet J
authors.initials: JJ
authors.lastname: Maguire
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Davenport
authors.forename: Martin
authors.initials: M
authors.lastname: Goddard
authors.forename: Martin R
authors.initials: MR
authors.lastname: Bennett
mesh_terms: D000199:Actins / Q000235:genetics; D019943:Amino Acid Substitution; D000818:Animals; D001013:Aorta, Thoracic / Q000473:pathology*; D001018:Aortic Diseases / Q000473:pathology*; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D017209:Apoptosis; D050197:Atherosclerosis / Q000150:complications / Q000235:genetics / Q000473:pathology*; D002114:Calcinosis / Q000150:complications / Q000473:pathology*; D003251:Constriction, Pathologic; D016207:Cytokines / Q000378:metabolism; D004167:Diphtheria Toxin / Q000633:toxicity; D018450:Disease Progression; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D015778:Minor Histocompatibility Antigens; D032389:Myocytes, Smooth Muscle / Q000473:pathology; D009336:Necrosis; D011993:Recombinant Fusion Proteins / Q000502:physiology; D025521:Tumor Suppressor Proteins; D017540:Tunica Media / Q000473:pathology*; D014661:Vasoconstriction
chemical_list: D000199:Actins; D001057:Apolipoproteins E; D016207:Cytokines; D004167:Diphtheria Toxin; C485679:Dph1 protein, mouse; C587883:HBEGF protein, human; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D015778:Minor Histocompatibility Antigens; D011993:Recombinant Fusion Proteins; D025521:Tumor Suppressor Proteins; C527526:diphtheria toxin-GMCSF fusino protein, recombinant