Characterization of primary and restenotic atherosclerotic plaque from the superficial femoral artery: Potential role of Smad3 in regulation of SMC proliferation.
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.


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 alpha-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 Smad3 decreased cell proliferation.


CONCLUSIONS
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.
Edlin
Rachel S
RS
Department of Surgery, Division of Vascular Surgery, New York Presbyterian Hospital and Weill Medical College of Cornell University, New York, NY, USA.
Tsai
Shirling
S
Yamanouchi
Dai
D
Wang
Chunjie
C
Liu
Bo
B
Kent
K Craig
KC
D017130:Angioplasty / Q000295:instrumentation; D017209:Apoptosis; D001157:Arterial Occlusive Diseases / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D017073:Atherectomy; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D049109:Cell Proliferation; D002478:Cells, Cultured; D003251:Constriction, Pathologic; D005263:Femoral Artery / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D006801:Humans; D006965:Hyperplasia; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D012008:Recurrence; D015398:Signal Transduction; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism*; D015607:Stents; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism; D016896:Treatment Outcome
C497790:SMAD3 protein, human; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta