Signal transduction in arteriosclerosis: mechanical stress-activated MAP kinases in vascular smooth muscle cells (review).
Vascular smooth muscle cell (SMC) proliferation is a key event in the development of (spontaneous) atherosclerosis, hypertension-related arteriosclerosis, angioplasty-induced restenosis and venous bypass graft arteriosclerosis. Many factors or environmental stimuli are believed to be responsible for SMC growth or hypertrophy in the vessel wall. How these environmental stimuli or signals applied onto the surface of SMCs are transduced into the cell nucleus resulting in quantitative and qualitative changes in gene expression in SMCs of arterial walls is largely unknown. Mitogen-activated protein (MAP) kinases are rapidly activated in cells stimulated with various extracellular signals by dual phosphorylation of tyrosine and threonine residues. They are thought to play a pivotal role in transmitting transmembrane signals required for cell growth and differentiation. Recent studies have focused on the signalling events in vascular tissues in vivo and in cultured SMCs in vitro. It has been demonstrated that acute hypertension and angioplasty rapidly induced MAP kinase activation in the arterial wall. Kinase activation is followed by an increase in c-fos and c-jun gene expression and enhanced transcription factor AP-1 DNA-binding activity. A similar MAP kinase activation can be mimicked in in vitro cultured SMCs stimulated by either shear stress or cyclic strain stretch, suggesting direct effects of mechanical force. Interestingly, physical forces rapidly resulted in phosphorylation of platelet-derived growth factor (PDGF) receptor, an activated state, in cultured SMCs. Thus, mechanical stresses may directly perturb the cell surface or alter receptor conformation, thereby initiating signalling pathways usually used by growth factors. These findings have significantly enhanced our knowledge concerning the pathogenesis of arteriosclerosis and provide a basis for therapeutic intervention on vascular diseases.
Zou
Y
Y
Institute for Biomedical Aging Research, Austrian Academy of Sciences, Innsbruck, Austria.
Hu
Y
Y
Metzler
B
B
Xu
Q
Q
D017130:Angioplasty / Q000009:adverse effects; D000818:Animals; D001161:Arteriosclerosis / Q000201:enzymology* / Q000378:metabolism*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002339:Carotid Arteries / Q000201:enzymology; D020212:Carotid Artery Injuries; D004195:Disease Models, Animal; D004789:Enzyme Activation; D006801:Humans; D006973:Hypertension / Q000201:enzymology; D009131:Muscle, Smooth, Vascular / Q000201:enzymology* / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D015398:Signal Transduction; D013314:Stress, Mechanical
D010982:Platelet-Derived Growth Factor; D017871:Calcium-Calmodulin-Dependent Protein Kinases