title: Smooth muscle cell-specific insulin-like growth factor-1 overexpression in Apoe-/- mice does not alter atherosclerotic plaque burden but increases features of plaque stability.
abstract: OBJECTIVE
  Growth factors may play a permissive role in atherosclerosis initiation and progression, in part via their promotion of vascular smooth muscle cell (VSMC) accumulation in plaques. However, unstable human plaques often have a relative paucity of VSMC, which has been suggested to contribute to plaque rupture and erosion and to clinical events. Insulin-like growth factor-1 (IGF-1) is an endocrine and autocrine/paracrine growth factor that is a mitogen for VSMC, but when infused into Apoe(-/-) mice it paradoxically reduces atherosclerosis burden.
  
  
  RESULTS
  To determine the effect of stimulation of VSMC growth on atherosclerotic plaque development and to understand mechanisms of IGF-1's atheroprotective effect, we assessed atherosclerotic plaques in mice overexpressing IGF-1 in smooth muscle cells (SMC) under the control of the α-smooth muscle actin promoter, after backcrossing to the Apoe(-/-) background (SMP8/Apoe(-/-)). Compared with Apoe(-/-) mice, these SMP8/Apoe(-/-) mice developed a comparable plaque burden after 12 weeks on a Western diet, suggesting that the ability of increased circulating IGF-1 to reduce plaque burden was mediated in large part via non-SMC target cells. However, advanced plaques in SMP8/Apoe(-/-) mice displayed several features of plaque stability, including increased fibrous cap area, α-smooth muscle actin-positive SMC and collagen content, and reduced necrotic cores.
  
  
  CONCLUSIONS
  These findings indicate that stimulation of VSMC IGF-1 signaling does not alter total atherosclerotic plaque burden and may improve atherosclerotic plaque stability.
authors.affiliation: Tulane University Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, La 70112, USA.
authors.forename: Shaw-Yung
authors.initials: SY
authors.lastname: Shai
authors.forename: Sergiy
authors.initials: S
authors.lastname: Sukhanov
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Higashi
authors.forename: Charlotte
authors.initials: C
authors.lastname: Vaughn
authors.forename: James
authors.initials: J
authors.lastname: Kelly
authors.forename: Patrice
authors.initials: P
authors.lastname: Delafontaine
mesh_terms: D000818:Animals; D001011:Aorta / Q000473:pathology / Q000503:physiopathology; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015870:Gene Expression; D006801:Humans; D006984:Hypertrophy; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D032389:Myocytes, Smooth Muscle / Q000473:pathology* / Q000502:physiology*; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D012333:RNA, Messenger; D011994:Recombinant Proteins; C548904:insulin-like growth factor-1, rat; D007334:Insulin-Like Growth Factor I