title: Paracrine effect of vascular smooth muscle cells in the prevention of aortic aneurysm formation.
abstract: OBJECTIVE
  Inflammation and elastinolysis are observed in the media of abdominal aortic aneurysms (AAAs) where vascular smooth muscle cell (VSMC) density is decreased. In contrast, elastin and VSMCs are preserved in the noninflammatory media of stenotic atherosclerotic lesions. We have tested the hypothesis that VSMCs exert a protective effect against inflammation and proteolysis in a model of AAA in rats, in which medial elastin degradation is driven by inflammation and matrix metalloproteinases.
  
  
  METHODS
  Decellularized guinea pig aortas (xenografts) were implanted orthotopically into Fischer-344 rats and seeded with a suspension of rat VSMCs syngeneic to the rat recipient, or were infused with culture medium as a control. Diameter and elastin in the media were quantified 8 weeks after implantation. Inflammation, matrix metalloproteinase (MMP) and tissue inhibitor of matrix metalloproteinase (TIMP) expression were analyzed 1 and 2 weeks after implantation.
  
  
  RESULTS
  VSMC addition prevented AAA formation (mean +/- standard deviation diameter increase: 198.2% +/- 106.6% vs 35.3% +/- 17.8%, P =.009), elastin degradation, and decreased infiltration by monocyte-macrophages. Reverse-transcriptase polymerase chain reaction, zymography and reverse zymography for MMP-2, MMP-9, TIMP-1, TIMP-2, and TIMP-3 demonstrated a shift of the proteolytic-antiproteolytic balance upon addition of VSMCs. Transcriptional changes were observed in the adventitia, although seeded VSMCs remained located in the intima.
  
  
  CONCLUSIONS
  VSMCs exert a paracrine effect on the adventitia that participate in artery wall homeostasis against inflammation and proteolysis. Failure of this protective mechanism results in AAA formation. The understanding of the molecular mechanisms underlying VSMC protective effect may represent a new approach in the treatment of aneurysm and plaque rupture.
authors.affiliation: CNRS UMR-A 7054, Centre de Recherches Chirurgicales, Créteil, France. allaire@lub-internet.fr
authors.forename: Eric
authors.initials: E
authors.lastname: Allaire
authors.forename: Béatrice
authors.initials: B
authors.lastname: Muscatelli-Groux
authors.forename: Chantal
authors.initials: C
authors.lastname: Mandet
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Guinault
authors.forename: Patrick
authors.initials: P
authors.lastname: Bruneval
authors.forename: Pascal
authors.initials: P
authors.lastname: Desgranges
authors.forename: Alexander
authors.initials: A
authors.lastname: Clowes
authors.forename: Didier
authors.initials: D
authors.lastname: Méllière
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Becquemin
mesh_terms: D000818:Animals; D001012:Aorta, Abdominal / Q000166:cytology / Q000637:transplantation; D017544:Aortic Aneurysm, Abdominal / Q000517:prevention & control*; D004549:Elastin / Q000378:metabolism; D006168:Guinea Pigs; D007249:Inflammation / Q000209:etiology; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D011480:Protease Inhibitors / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: D011480:Protease Inhibitors; D012333:RNA, Messenger; D019714:Tissue Inhibitor of Metalloproteinases; D004549:Elastin; D020782:Matrix Metalloproteinases