© 1996 American Heart Association, Inc.
Articles |
MAP Kinase Activation by Flow in Endothelial Cells
Role of ß1 Integrins and Tyrosine Kinases
the Department of Medicine, Cardiology and Hematology (N.L.K.) Divisions, University of Washington, Seattle. This manuscript was sent to Francois M. Abboud, Consulting Editor, for review by expert referees, editorial decision, and final disposition.
Correspondence to Bradford C. Berk, MD, PhD, Cardiology Division, Box 357710, University of Washington, Seattle, WA 98195. E-mail bcberk@u.washington.edu.
Local alterations in the hemodynamic environment regulate endothelial cell function, but the signal-transduction mechanisms involved in this process remain unclear. We previously demonstrated that mitogen-activated protein (MAP) kinase is rapidly stimulated by flow in bovine aortic endothelial cells. Integrin receptors may act as mechanotransducers, as suggested by rapid remodeling of focal adhesion complexes in response to flow. To study the role of integrins in flow-mediated MAP kinase activation, we compared the effects of ß1 integrin activation (with 8A2 antibody) and flow in cultured human umbilical vein endothelial cells (HUVECs). Both 8A2 (3 µg/mL) and flow (shear stress, 12 dynes/cm2) stimulated MAP kinase, although the flow response was faster and greater. To characterize flow-activated tyrosine kinases, tyrosine-phosphorylated proteins were immunoprecipitated and identified by Western blot. There was a time-dependent increase in phosphotyrosine content in 60- to 80-kD, 110-kD, 125- to 150-kD, and 180- to 190-kD proteins. A 125-kD protein was identified as focal adhesion kinase (FAK), suggesting that flow activates integrins. In comparison with flow, 8A2 caused less tyrosine phosphorylation of fewer proteins, although FAK was tyrosine phosphorylated. Concurrent stimulation of HUVECs with 8A2 and flow caused additive increases in MAP kinase. Antibody 8A2 increased binding of the ß1 affinity–sensitive antibody, 15/7, while flow failed to increase binding of 15/7. In summary, both a ß1-activating antibody and flow stimulate tyrosine kinases, leading to activation of FAK and MAP kinase signal-transduction pathways. However, the cellular responses elicited by 8A2 represent only a portion of those stimulated by flow, suggesting that "costimulatory" events such as calcium mobilization, in addition to integrin activation, mediate the HUVEC response to fluid shear stress.
Key Words: MAP kinase • signal transduction • endothelial cells
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