Interstitial flow induces MMP-1 expression and vascular SMC migration in collagen I gels via an ERK1/2-dependent and c-Jun-mediated mechanism.
The migration of vascular smooth muscle cells (SMCs) and fibroblasts into the intima after vascular injury is a central process in vascular lesion formation. The elevation of transmural interstitial flow is also observed after damage to the vascular endothelium. We have previously shown that interstitial flow upregulates matrix metalloproteinase-1 (MMP-1) expression, which in turn promotes SMC and fibroblast migration in collagen I gels. In this study, we investigated further the mechanism of flow-induced MMP-1 expression. An ERK1/2 inhibitor PD-98059 completely abolished interstitial flow-induced SMC migration and MMP-1 expression. Interstitial flow promoted ERK1/2 phosphorylation, whereas PD-98059 abolished flow-induced activation. Silencing ERK1/2 completely abolished MMP-1 expression and SMC migration. In addition, interstitial flow increased the expression of activator protein-1 transcription factors (c-Jun and c-Fos), whereas PD-98059 attenuated flow-induced expression. Knocking down c-jun completely abolished flow-induced MMP-1 expression, whereas silencing c-fos did not affect MMP-1 expression. Taken together, our data indicate that interstitial flow induces MMP-1 expression and SMC migration in collagen I gels via an ERK1/2-dependent and c-Jun-mediated mechanism and suggest that interstitial flow, ERK1/2 MAPK, c-Jun, and MMP-1 may play important roles in SMC migration and neointima formation after vascular injury.
Shi
Zhong-Dong
ZD
City College of New York, City University of New York, Department of Biomedical Engineering, New York, NY 10031, USA. zdshi@hotmail.com
Ji
Xin-Ying
XY
Berardi
Danielle E
DE
Qazi
Henry
H
Tarbell
John M
JM
D000818:Animals; D015153:Blotting, Western; D002469:Cell Separation; D024042:Collagen Type I / Q000737:chemistry; D017931:DNA Primers; D004789:Enzyme Activation / Q000502:physiology; D045604:Extracellular Fluid / Q000502:physiology*; D005782:Gels; D020868:Gene Silencing; D016762:Genes, fos / Q000235:genetics / Q000502:physiology; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000502:physiology; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis*; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000502:physiology*; D032389:Myocytes, Smooth Muscle / Q000502:physiology*; D016755:Proto-Oncogene Proteins c-jun / Q000502:physiology*; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000502:physiology
D024042:Collagen Type I; D017931:DNA Primers; D005782:Gels; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D012313:RNA; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020781:Matrix Metalloproteinase 1