Journal
JOURNAL OF VASCULAR SURGERY
Volume 49, Issue 5, Pages 1289-1295Publisher
MOSBY-ELSEVIER
DOI: 10.1016/j.jvs.2008.11.096
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Funding
- Public Health Service Grant [R01 H1-68673]
- National Heart, Lung, and Blood Institute, an American Heart Association [0455859T]
- National Institutes of Health [F32 HL088818-01]
- Society of University Surgeons-Ethicon Scholarship Grant Award
- Uehara Memorial Foundation Research Fellowship Award
- Howard Hughes Medical Institute Medical Research Training Fellowship
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Objective: To characterize and compare primary and restenotic lesions of the superficial femoral artery and analyze the contribution of TGF-beta/Smad3 signaling to the pathophysiology of peripheral artery occlusive disease. Methods and Results. Immunohistochemical studies were performed on specimens retrieved from the superficial femoral artery of patients undergoing either atherectomy for primary atherosclerotic or recurrent disease after stenting and/or prior angioplasty. Immunohistochemical analysis revealed a significantly higher smooth muscle cell (SMC) content (alpha-actin+) and expression of Smad3 in restenotic lesions while primary lesions contained significantly more leukocytes (CD45+) and macrophages (CD68+). Further studies demonstrated colocalization of Smad3 with a-actin and PCNA, suggesting a role for Smad3 in the proliferation observed in restenotic lesions. To confirm a role for Smad3 in SMC proliferation, we both upregulated Smad3 via adenoviral mediated gene transfer (AdSmad3) and inhibited Smad3 through transfection with siRNA in human aortic SMCs, then assessed cell proliferation with tritiated thymidine. Overexpression of Smad3 enhanced whereas inhibition of Srnad3 decreased cell proliferation. Conclusion: Differences in cellular composition and cell proliferation in conjunction with the finding that Smad3 is expressed exclusively in restenotic disease suggest that TGF-beta, through Smad3 signaling, may play an essential role in SMC proliferation and the pathophysiology of restenosis in humans. (J Vasc Surg 2009;49:1289-95.)
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