Angiotensin II-dependent growth of vascular smooth muscle cells requires transactivation of the epidermal growth factor receptor via a cytosolic phospholipase A2-mediated release of arachidonic acid

Angiotensin (Ang) II stimulates vascular smooth muscle cell (VSMC) growth via activation of cytosolic phospholipase A₂ (cPLA₂), release of arachidonic acid (ArAc) and activation of mitogen-activated protein kinase (MAPK). The mechanism linking AT₁ receptor stimulation of ArAc release with MAPK activation may involve transactivation of the epidermal growth factor receptor (EGFR). In this study, Ang II increased phosphorylation of the EGFR and MAPK in cultured VSMC and these effects were attenuated by the cPLA₂ inhibitor arachidonyl trifluoromethyl ketone (AACOCF₃), and restored by addition of ArAc. Ang II- or ArAc-induced phosphorylation of the EGFR and MAPK were abolished by the EGFR kinase inhibitor AG1478. Ang II or ArAc also stimulated VSMC growth that was blocked by AG1478 or the MAPK kinase (MEK) inhibitor PD98059. Thus, it appears that the cPLA₂-dependent release of ArAc may provide a mechanism for the transactivation between the AT₁ receptor and the EGFR signaling cascade.