Injury induces dedifferentiation of smooth muscle cells and increased matrix-degrading metalloproteinase activity in human saphenous vein.
Long-term patency of human saphenous vein bypass grafts is low because of intimal thickening and superimposed atherosclerosis. Matrix-degrading metalloproteinases (MMPs) and changes in vascular smooth muscle cell (VSMC) phenotype are thought to be essential for the VSMC migration that contributes to intimal thickening. We examined VSMC phenotype and MMP activity in saphenous veins obtained before and after surgical manipulation. Surgical preparation of the veins significantly increased pro-MMP-1 expression by 2-fold and significantly reduced tissue inhibitor of MMPs (TIMP)-2 expression, whereas MMP-3 and TIMP-1 were unaffected. Furthermore, caseinolytic and gelatinolytic activities measured by in situ zymography were dramatically elevated by injury. The expression of desmin and smoothelin was significantly decreased by injury, whereas vimentin expression was significantly increased. In addition, these changes in phenotype and MMP activity were localized to a subpopulation of VSMCs, the circumferential medial VSMCs. Our data show that surgical preparative injury induces phenotypic modulation of a subpopulation of medial VSMCs to a synthetic phenotype and increases MMP activity. This may favor matrix degradation, VSMC migration, and the subsequent intimal thickening that leads to graft failure.
Johnson
J L
JL
Bristol Heart Institute, University of Bristol, Bristol, UK. jason.l.johnson@bris.ac.uk
van Eys
G J
GJ
Angelini
G D
GD
George
S J
SJ
D002364:Caseins / Q000378:metabolism; D002454:Cell Differentiation; D001026:Coronary Artery Bypass; D003598:Cytoskeletal Proteins / Q000378:metabolism; D003893:Desmin / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D005780:Gelatin / Q000378:metabolism; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism*; D009124:Muscle Proteins / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000201:enzymology* / Q000502:physiology*; D010641:Phenotype; D012501:Saphenous Vein / Q000293:injuries*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D014746:Vimentin / Q000378:metabolism
D002364:Caseins; D003598:Cytoskeletal Proteins; D003893:Desmin; D009124:Muscle Proteins; C100762:SMTN protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D014746:Vimentin; D019716:Tissue Inhibitor of Metalloproteinase-2; D005780:Gelatin; D019278:Matrix Metalloproteinase 3; D020781:Matrix Metalloproteinase 1