Hepatocyte growth factor triggers signaling cascades mediating vascular smooth muscle cell migration.
A key event in neointima formation and atherogenesis is the migration of vascular smooth muscle cells (VSMCs) into the intima. This is controlled by cytokines and extracellular matix (ECM) components within the microenvironment of the diseased vessel wall. At present, these signals have only been partially identified. In this study, we demonstrate that Met, the receptor tyrosine kinase for hepatocyte growth factor (HGF), is expressed on VSMCs isolated from the intima of atherosclerotic plaques of carotid arteries. Stimulation with HGF led to activation of Met as well as to activation of PI3-K, PKB/Akt, MEK, and the MAP kinases Erk1 and -2. Moreover, HGF induced lamellipodia formation, a characteristic feature of motile cells, and promoted VSMC migration across fibronectin-coated filters. The HGF-induced cell migration was mediated by beta1 integrins and required PI3-K activation. Our results suggest a role for the HGF-Met signaling pathway in the pathogenesis of atherosclerosis and restenosis.
Taher
Taher E I
TE
Department of Pathology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
Derksen
Patrick W B
PW
de Boer
Onno J
OJ
Spaargaren
Marcel
M
Teeling
Peter
P
van der Wal
Allard C
AC
Pals
Steven T
ST
D001161:Arteriosclerosis / Q000378:metabolism / Q000503:physiopathology*; D002339:Carotid Arteries / Q000166:cytology / Q000378:metabolism / Q000503:physiopathology; D002465:Cell Movement; D002478:Cells, Cultured; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006801:Humans; D016023:Integrins / Q000502:physiology; D020935:MAP Kinase Signaling System; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000503:physiopathology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D011554:Pseudopodia / Q000648:ultrastructure; D015398:Signal Transduction
D017228:Hepatocyte Growth Factor; D016023:Integrins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D019859:Proto-Oncogene Proteins c-met; D016283:Proto-Oncogene Proteins p21(ras); C494918:AKT1 protein, human; C501009:HRAS protein, human