Molecular Mechanisms of Collagen Isotype-Specific Modulation of Smooth Muscle Cell Phenotype.

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Molecular Mechanisms of Collagen Isotype-Specific Modulation of Smooth Muscle Cell Phenotype. / Orr, A Wayne; Lee, Monica Y; Lemmon, Julia A; Yurdagul, Arif; Gomez, Maria; Schoppee Bortz, Pamela D; Wamhoff, Brian R.

I: Arteriosclerosis, Thrombosis and Vascular Biology, Vol. Nov 20, 2009, s. 225-231.

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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Orr, A Wayne ; Lee, Monica Y ; Lemmon, Julia A ; Yurdagul, Arif ; Gomez, Maria ; Schoppee Bortz, Pamela D ; Wamhoff, Brian R. / Molecular Mechanisms of Collagen Isotype-Specific Modulation of Smooth Muscle Cell Phenotype. I: Arteriosclerosis, Thrombosis and Vascular Biology. 2009 ; Vol. Nov 20. s. 225-231.

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TY - JOUR

T1 - Molecular Mechanisms of Collagen Isotype-Specific Modulation of Smooth Muscle Cell Phenotype.

AU - Orr, A Wayne

AU - Lee, Monica Y

AU - Lemmon, Julia A

AU - Yurdagul, Arif

AU - Gomez, Maria

AU - Schoppee Bortz, Pamela D

AU - Wamhoff, Brian R

PY - 2009

Y1 - 2009

N2 - 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. METHODS AND 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.

AB - 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. METHODS AND 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.

U2 - 10.1161/ATVBAHA.108.178749

DO - 10.1161/ATVBAHA.108.178749

M3 - Article

C2 - 19023090

VL - Nov 20

SP - 225

EP - 231

JO - Arteriosclerosis, Thrombosis and Vascular Biology

JF - Arteriosclerosis, Thrombosis and Vascular Biology

SN - 1524-4636

ER -