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) α, an activated state. When GRB2, an adapter protein, was immunoprecipitated from treated VSMCs followed by Western blot analysis with anti‐phosphotyrosine, ‐PDGFRα, and ‐GRB2 antibodies, respectively, phosphotyrosine positive staining was observed on PDGFRα bands of the same blot in stretch‐stressed VSMCs, supporting the mechanical stress‐induced activation of PDGFRα. Conditioned medium from stretch‐stressed VSMCs did not result in PDGFRα phosphorylation, and antibodies binding to all forms of PDGFs did not block stress‐induced PDGFRα 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., Böck, Güunther, Wick, G., Xu, Q., Activation of PDGF receptor α in vascular smooth muscle cells by mechanical stress. FASEB J. 12, 1135–1142 (1998)