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Transactivation of epidermal growth factor receptor mediates catecholamine-induced growth of vascular smooth muscle

Hua Zhang1, Dan Chalothorn, Leslie F Jackson

  • 1Department of Cell and Molecular Physiology, School of Medicine, University of North Carolina, Chapel Hill, NC 27599-7545, USA.

Circulation Research
|October 16, 2004
PubMed

Insights

Alpha1-adrenoceptor stimulation drives vascular smooth muscle cell growth via epidermal growth factor receptor (EGFR) transactivation and extracellular regulated kinases (ERK) signaling. This pathway involves reactive oxygen species (ROS) and heparin-binding EGF-like growth factor (HB-EGF) release.

Area of Science:

  • Cardiovascular Biology
  • Cell Signaling
  • Molecular Medicine

Background:

  • Alpha1-adrenoceptors regulate vascular smooth muscle cell (SMC) proliferation and arterial remodeling.
  • NAD(P)H oxidase and reactive oxygen species (ROS) are implicated, but the precise pathway remains unclear.
  • This study investigates the role of epidermal growth factor receptor (EGFR) transactivation and extracellular regulated kinases (ERK) in this process.

Purpose of the Study:

  • To examine the hypothesis that EGFR transactivation and ERK are involved in alpha1-adrenoceptor-mediated SMC growth.
  • To elucidate the signaling cascade linking alpha1-adrenoceptor stimulation to SMC proliferation.

Main Methods:

  • Organ culture of rat aorta and primary rat SMCs.
  • Stimulation with phenylephrine (alpha1-adrenoceptor agonist).
  • Assessment of protein synthesis, EGFR and ERK phosphorylation, ROS generation, and the effects of specific antagonists and genetic manipulation (HB-EGF-/- SMCs).

Main Results:

  • Phenylephrine rapidly increased EGFR and ERK1/2 phosphorylation, but not p38 or JNK.
  • EGFR and ERK antagonists abolished phenylephrine-induced protein synthesis.
  • Heparin-binding EGF-like growth factor (HB-EGF) release, mediated by metalloproteinases, was essential for phenylephrine-induced SMC growth.
  • ROS generation preceded HB-EGF release, indicating a sequential pathway.

Conclusions:

  • Alpha1-adrenoceptor-mediated SMC growth is dependent on ROS-induced HB-EGF shedding.
  • This process involves EGFR transactivation and MEK1/2-dependent ERK activation.
  • This pathway links sympathetic activity to arterial wall growth in remodeling and disease.

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