Activation of PDGF receptor alpha in vascular smooth muscle cells by mechanical stress.
Hypertension increases mechanical force on the arterial wall by as much as 30%, resulting in marked alterations in signal transductions and gene expression in vascular smooth muscle cells (VSMCs) that contribute to matrix protein synthesis, cell proliferation, and differentiation. How the mechanical stimuli are converted into a biological signal in cells has yet to be studied. We investigated the role of both cyclic strain and shear stresses in initiating the cellular signaling on cultured VSMCs and found that mechanical forces evoked activation of mitogen-activated protein kinases, followed by enhanced DNA binding activity of transcription factor AP-1. Physical forces rapidly induced phosphorylation of platelet-derived growth factor receptor (PDGFR) alpha, an activated state. When GRB2, an adapter protein, was immunoprecipitated from treated VSMCs followed by Western blot analysis with anti-phosphotyrosine, -PDGFR alpha, and -GRB2 antibodies, respectively, phosphotyrosine positive staining was observed on PDGFR alpha bands of the same blot in stretch-stressed VSMCs, supporting the mechanical stress-induced activation of PDGFR alpha. Conditioned medium from stretch-stressed VSMCs did not result in PDGFR alpha phosphorylation, and antibodies binding to all forms of PDGFs did not block stress-induced PDGFR alpha activation. Thus, mechanical stresses may directly perturb the cell surface or alter receptor conformation, thereby initiating signaling pathways normally used by growth factors.
Hu
Y
Y
Institute for Biomedical Aging Research, Austrian Academy of Sciences, Innsbruck.
Böck
G
G
Wick
G
G
Xu
Q
Q
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001011:Aorta; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002478:Cells, Cultured; D051380:GRB2 Adaptor Protein; D007700:Kinetics; D019950:Mitogen-Activated Protein Kinase 1; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000502:physiology*; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology / Q000502:physiology; D011506:Proteins / Q000378:metabolism; D051381:Rats; D020796:Receptor, Platelet-Derived Growth Factor alpha; D017479:Receptors, Platelet-Derived Growth Factor / Q000302:isolation & purification / Q000378:metabolism*; D015398:Signal Transduction; D013314:Stress, Mechanical; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; C495950:Grb2 protein, rat; D010982:Platelet-Derived Growth Factor; D011506:Proteins; D018808:Transcription Factor AP-1; D020796:Receptor, Platelet-Derived Growth Factor alpha; D017479:Receptors, Platelet-Derived Growth Factor; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1