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(Circulation Research. 2004;95:989.)
© 2004 American Heart Association, Inc.

Molecular Medicine

Transactivation of Epidermal Growth Factor Receptor Mediates Catecholamine-Induced Growth of Vascular Smooth Muscle

Hua Zhang, Dan Chalothorn, Leslie F. Jackson, David C. Lee, James E. Faber

From the Departments of Cell and Molecular Physiology (H.Z., D.C., J.E.F.) and Biochemistry and Biophysics (L.F.J., D.C.L.), School of Medicine, University of North Carolina, Chapel Hill.

Correspondence to James Faber, Department of Cell and Molecular Physiology, School of Medicine, University of North Carolina, Chapel Hill, NC 27599-7545. E-mail jefaber{at}med.unc.edu

Stimulation of ₁-adrenoceptors induces proliferation of vascular smooth muscle cells (SMCs) and contributes to arterial remodeling. Although activation of NAD(P)H oxidase and generation of reactive oxygen species (ROS) are required, little is known about this pathway. In this study, we examined the hypothesis that epidermal growth factor receptor (EGFR) transactivation and extracellular regulated kinases (ERK) are involved in ₁-adrenoceptor–mediated SMC growth. Phenylephrine increased protein synthesis in association with a rapid (5 minutes) and sustained (60 minutes) doubling of phosphorylation of EGFR and ERK1/2, but not p38 or JNK in the media of rat aorta maintained in organ culture. Antagonists of EGFR phosphotyrosine activity (AG-1478) and ERK phosphorylation (PD-98059, U-0126) abolished phenylephrine-induced protein synthesis, whereas antagonists of p38 or JNK phosphorylation had no specific effect. A competitive antagonist (P22) for heparin binding EGF-like growth factor (HB-EGF) blocked phenylephrine-induced protein synthesis, as did downregulation of pro-HB-EGF (CRM197). Phenylephrine-induced protein synthesis was inhibited by neutralizing antibody to HB-EGF and absent in HB-EGF^–/– SMCs. Inhibitors of metalloproteinases (BiPS, KB-R7785) also blocked adrenergic growth. The neutralizing antibody against HB-EGF had no effect on the two-fold increase in ROS generation induced by phenylephrine (DCF fluorescence), suggesting that stimulation of NAD(P)H oxidase by ₁-adrenoceptor occupation precedes HB-EGF release. Cell culture studies confirmed and extended these findings. These data suggest that ₁-adrenoceptor–mediated SMC growth requires ROS-dependent shedding of HB-EGF, transactivation of EGFR, and activation of the MEK1/2-dependent MAP kinase pathway. This trophic pathway may link sympathetic activity to arterial wall growth in adaptive remodeling and hypertrophic disease.

Key Words: -adrenergic receptor • vascular smooth muscle cell proliferation • signal transduction • reactive oxygen species • metalloproteinase

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