Paracrine secretion of transforming growth factor-beta1 in aneurysm healing and stabilization with endovascular smooth muscle cell therapy.
BACKGROUND
Identification of molecular factors involved in artery wall stabilization after extracellular matrix injury elicited by inflammation and proteolysis has a major role in the development of new therapies for atherosclerosis. A study from our group demonstrated that endovascular seeding of vascular smooth muscle cells (VSMCs) promotes healing and stabilizes experimental aneurysms by downregulating matrix metalloproteinase and upregulating tissue inhibitor of metalloproteinase and collagen gene expression. We analyzed expression of transforming growth factor-beta (TGF-beta) and its receptors in experimental aneurysms treated with endovascular VSMC therapy.


RESULTS
Aneurysms were generated in Fischer 344 rats by 14-day orthotopic implantation of a segment of guinea pig abdominal aorta (xenograft). During an endovascular repeat operation, syngeneic VSMCs were seeded in the aneurysm, always resulting in aneurysm diameter stabilization after 8 weeks, whereas diameter of control aneurysms infused with culture medium further increased. Seven days after repeat operation the intima or thrombus was separated from the aneurysmal wall in the two groups. Reverse transcriptase polymerase chain reaction with the domestic gene 18s as a standard demonstrated that aneurysm stabilization was associated with a statistically significant increase in TGF-beta(1), but not TGF-beta(2) or TGF-beta(3), messenger RNA levels in the intima. Enzyme-linked immunosorbent assay demonstrated increased TGF-beta(1) protein in the aneurysmal wall. mRNA levels of the two serine and threonine kinase TGF-beta receptors remained unchanged.


CONCLUSIONS
Healing and stabilization of aneurysms with endovascular cell therapy is associated with a specific pattern of gene expression, resulting in paracrine secretion of TGF-beta(1). Our study provides insight into the molecular mechanisms of arterial aneurysm healing and stabilization.
Losy
Franck
F
Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche (UMR) 7054, Centre de Recherches Chirurgicales, Université Paris XII, UFR de Médecine, Hôpital Henri Mondor, Créteil and Paris, France.
Dai
Jianping
J
Pages
Carine
C
Ginat
Maryvonne
M
Muscatelli-Groux
Béatrice
B
Guinault
Anne-Marie
AM
Rousselle
Elodie
E
Smedile
Gianluca
G
Loisance
Daniel
D
Becquemin
Jean-Pierre
JP
Allaire
Eric
E
D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D064987:Cell- and Tissue-Based Therapy; D004195:Disease Models, Animal; D015870:Gene Expression / Q000235:genetics / Q000502:physiology; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000473:pathology* / Q000502:physiology*; D019899:Paracrine Communication / Q000235:genetics / Q000502:physiology*; D051381:Rats; D011916:Rats, Inbred F344; D018125:Receptors, Transforming Growth Factor beta / Q000032:analysis / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000032:analysis* / Q000235:genetics; D053773:Transforming Growth Factor beta1; D014945:Wound Healing / Q000502:physiology*
D018125:Receptors, Transforming Growth Factor beta; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1