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(Hypertension. 2002;39:502.)
© 2002 American Heart Association, Inc.

Scientific Contributions

Src Autophosphorylation is an Early Event in Pressure-Mediated Signaling Pathways in Isolated Resistance Arteries

Darian C. Rice; Anca D. Dobrian; Suzanne D. Schriver; Russell L. Prewitt

From the Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, Va.

Correspondence to Darian C. Rice, MD, or Russell L. Prewitt, PhD, Eastern Virginia Medical School, Department of Physiological Sciences, Lewis Hall, Room 2013, 700 W. Olney Road, Norfolk, VA 23507. E-mail prewitrj{at}evms.edu

Abstract— Elevated blood pressure is associated with varying degrees of arterial growth and remodeling. The mechanisms by which mechanical stress is converted into cellular alteration have yet to be fully elucidated. Our laboratory has demonstrated that Src tyrosine kinases and the extracellular signal-regulated kinase subtype of the mitogen-activated protein kinase family mediate pressure-induced c-fos expression in rat mesenteric arteries. Others have reported involvement of integrin and growth factor receptor signaling pathways. Our goal was to determine the role of Src, focal adhesion kinase (FAK), and platelet-derived growth factor (PDGF) receptor signaling in the upstream initiation of these events. Pairs of rat mesenteric arteries were pressurized to 90 mm Hg (control), and then one was raised to 140 mm Hg for 1, 3, or 5 minutes. Western blotting revealed that Src-pY₄₁₈ was elevated 2.4-fold over control values at 1 minute and 2.8-fold at 3 minutes and returned to control at 5 minutes. Significant FAK-Y³⁹⁷ phosphorylation was observed only after 3 and 5 minutes of pressure stimulus and was blocked entirely by Src inhibition. Src-pY²¹⁵ activity (associated with PDGF receptor activation) does not seem to be involved at any of the time points tested. These data demonstrate that Src-Y⁴¹⁸ autophosphorylation is an early event in pressure mechanotransduction and leads to activation of FAK-Y³⁹⁷. This finding suggests that Src may be the messenger that initiates and propagates the cellular growth response to pressure stimulus, and FAK is one of its downstream targets. Src phosphorylation due to PDGF receptor activation does not seem to be involved in the initial response.

Key Words: hypertension, chronic • signal transduction • arteries • remodeling • kinase • platelet-derived growth factor

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