Paracrine secretion of transforming growth factor-β1 in aneurysm healing and stabilization with endovascular smooth muscle cell therapy1

Abstract 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-β) and its receptors in experimental aneurysms treated with endovascular VSMC therapy. Methods and 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-β 1 , but not TGF-β 2 or TGF-β 3 , messenger RNA levels in the intima. Enzyme-linked immunosorbent assay demonstrated increased TGF-β 1 protein in the aneurysmal wall. mRNA levels of the two serine and threonine kinase TGF-β 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-β 1 . Our study provides insight into the molecular mechanisms of arterial aneurysm healing and stabilization.