Paracrine effect of vascular smooth muscle cells in the prevention of aortic aneurysm formation.
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.
Allaire
Eric
E
CNRS UMR-A 7054, Centre de Recherches Chirurgicales, Créteil, France. allaire@lub-internet.fr
Muscatelli-Groux
Béatrice
B
Mandet
Chantal
C
Guinault
Anne-Marie
AM
Bruneval
Patrick
P
Desgranges
Pascal
P
Clowes
Alexander
A
Méllière
Didier
D
Becquemin
Jean-Pierre
JP
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
D011480:Protease Inhibitors; D012333:RNA, Messenger; D019714:Tissue Inhibitor of Metalloproteinases; D004549:Elastin; D020782:Matrix Metalloproteinases