Involvement of epidermal growth factor receptor—protein tyrosine kinase transactivation in endothelin-1—induced vascular contraction

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Abstract
Object.Endothelin-1 (ET-1) is one of the major inducers of vasospasm following subarachnoid hemorrhage (SAH). It is generally accepted that extracellular signal—regulated kinase 1 and 2 (ERK1/2) are involved in ET-1—induced vascular contraction. In addition, ET-1 transactivates epidermal growth factor receptor (EGFR) protein tyrosine kinase (PTK), which leads to ERK1/2 stimulation. Therefore, the authors examined whether EGFR—PTK transactivation contributes to ET-1—induced vascular contraction in this study.Methods.Mitogen-activated protein kinase inhibitor, PD98059, inhibited ET-1—induced ERK1/2 stimulation in rabbit basilar artery (BA) vascular smooth-muscle cells (VSMCs). Moreover, PD98059 inhibited ET-1—induced contraction of rabbit BA rings. A specific inhibitor of EGFR PTK, AG1478, inhibited ET-1—induced EGFR—PTK transactivation, ERK1/2 stimulation, and contraction of BA rings in a concentration-dependent manner. The concentration of AG1478 required for 50% inhibition of the ET-1—induced contraction of BA rings was similar to that for ET-1—induced EGFR—PTK transactivation. Furthermore, AG1478 also inhibited ET-1—induced BA vasospasm in vivo.Conclusion.The results indicate that EGFR—PTK transactivation pathway plays an important role in ET-1—induced vascular contraction.

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