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Smooth Muscle Cells From Spontaneously Hypertensive Rats Transactivation Is Associated With Decreased C-Terminal Src Kinase Activity in Vascular Increased Angiotensin II-Mediated Src Signaling via Epidermal Growth Factor Receptor

We investigated whether upregulation of Src by Ang II leads to increased extracellular signal–regulated kinase 1/2 (ERK1/2) phosphorylation in vascular smooth muscle cells (VSMCs) from spontaneously hypertensive rats (SHR) and whether these processes are associated with altered activation of C-terminal Src kinase (Csk), a negative regulator of Src. Furthermore, the role of epidermal growth factor receptor (EGFR) transactivation by angiotensin II (Ang II) was determined. Ang II–mediated c-Src phosphorylation was significantly greater ( 4-fold, P 0.01) in SHR than in Wistar-Kyoto rats (WKY). Ang II increased Csk phosphorylation 2-to 3-fold in WKY but not in SHR. Treatment of the cells with AG1478, a selective EGFR tyrosine kinase inhibitor, decreased Ang II–mediated c-Src phosphorylation, particularly in SHR. Phosphorylation of cortactin and Pyk2/focal adhesion kinase, Src-specific substrates, was increased by Ang II 3-fold, with significantly greater responses in SHR than in WKY (P 0.05). Ang II–induced ERK1/2 activation was significantly augmented (P 0.05) and sustained in VSMCs from SHR. PP2, a selective Src inhibitor, attenuated these effects and normalized the responses in SHR. Irbesartan, a selective Ang II type 1 receptor blocker, but not PD123319, a selective Ang II type 2 receptor blocker, inhibited Ang II actions. Our results demonstrate that c-Src phosphorylation and Src-dependent ERK1/2 signaling by Ang II are increased in VSMCs from SHR. These processes are associated with blunted Ang II–induced phosphorylation of Csk. EGFR transactivation contributes to Ang II–mediated Src-dependent ERK1/2 signaling. In conclusion, altered regulation of Ang II type 1 receptor–activated c-Src by Csk may be an important upstream modulator of abnormal ERK1/2 signaling in VSMCs from SHR. (Hypertension. 2002;39[part 2]:479-485.)