Molecular mechanisms of collagen isotype-specific modulation of smooth muscle cell phenotype.
OBJECTIVE
Smooth muscle cell (SMC) phenotypic modulation, an important component of atherosclerosis progression, is critically regulated by the matrix, with normal components of the healthy SMC matrix limiting modulation and atherosclerosis-associated transitional matrix proteins promoting phenotypic modulation. We sought to determine how collagen IV (which comprises the healthy artery wall) and monomeric collagen I (which comprises atherosclerotic lesions) differentially affect SMC phenotype.


RESULTS
Plating SMCs on collagen IV resulted in elevated expression of SMC contractility proteins compared to collagen I. Concurrent with enhanced contractile gene expression, collagen IV stimulates binding of SRF to CArG boxes in the promoters of smooth muscle actin and smooth muscle myosin heavy chain. Coll IV also stimulated the expression of myocardin, a critical SRF coactivator required to drive expression of SMC specific genes. In contrast to collagen IV, collagen I stimulated enhanced expression of the inflammatory protein vascular cell adhesion molecule (VCAM)-1. NF-kappaB and NFAT-binding sites in the VCAM-1 promoter are critical for collagen I-mediated expression of VCAM-1 promoter activity. However, only inhibitors of NFAT, not NF-kappaB, were able to reduce collagen I-associated VCAM expression, and collagen I but not collagen IV stimulated NFAT transcriptional activity.


CONCLUSIONS
These results show for the first time that collagen IV and collagen I differentially affect smooth muscle phenotypic modulation through multiple pathways.
Orr
A Wayne
AW
Department of Pathology, Louisiana State University Health Sciences Center at Shreveport, USA.
Lee
Monica Y
MY
Lemmon
Julia A
JA
Yurdagul
Arif
A
Gomez
Maria F
MF
Bortz
Pamela D Schoppee
PD
Wamhoff
Brian R
BR
D000818:Animals; D001011:Aorta / Q000378:metabolism*; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism*; D019703:Calcineurin / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism*; D024141:Collagen Type IV / Q000378:metabolism*; D005786:Gene Expression Regulation; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000378:metabolism; D010641:Phenotype; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D027602:Serum Response Element; D026362:Serum Response Factor / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D024042:Collagen Type I; D024141:Collagen Type IV; D009124:Muscle Proteins; D050778:NFATC Transcription Factors; D020033:Protein Isoforms; D012333:RNA, Messenger; D026362:Serum Response Factor; D019010:Vascular Cell Adhesion Molecule-1; D019703:Calcineurin