Transactivation of epidermal growth factor receptor mediates catecholamine-induced growth of vascular smooth muscle.
Stimulation of alpha1-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 alpha1-adrenoceptor-mediated SMC growth. Phenylephrine increased protein synthesis in association with a rapid (< or =5 minutes) and sustained (> or =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 alpha1-adrenoceptor occupation precedes HB-EGF release. Cell culture studies confirmed and extended these findings. These data suggest that alpha1-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.
Department of Cell and Molecular Physiology, School of Medicine, University of North Carolina, Chapel Hill, NC 27599-7545, USA.
Hua
H
Zhang
Dan
D
Chalothorn
Leslie F
LF
Jackson
David C
DC
Lee
James E
JE
Faber
D058646:Adrenergic alpha-1 Receptor Agonists; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D001013:Aorta, Thoracic / Q000293:injuries / Q000473:pathology; D001426:Bacterial Proteins / Q000494:pharmacology; D001578:Benzopyrans / Q000494:pharmacology; D002070:Butadienes / Q000494:pharmacology; D002404:Catheterization / Q000009:adverse effects; D002455:Cell Division; D004151:Dipeptides / Q000494:pharmacology; D066246:ErbB Receptors / Q000187:drug effects / Q000502:physiology*; D005419:Flavonoids / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006877:Hydroxamic Acids / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D048369:MAP Kinase Kinase 1 / Q000502:physiology; D048370:MAP Kinase Kinase 2 / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology; D048052:Mitogen-Activated Protein Kinase 3 / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D009570:Nitriles / Q000494:pharmacology; D009924:Organ Culture Techniques; D010656:Phenylephrine / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D011799:Quinazolines; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000502:physiology*; D013917:Thrombin / Q000494:pharmacology; D020032:Tyrphostins / Q000494:pharmacology
C483331:1',3-dihydro-1'-(2-carboxyethyl)-3,3-dimethyl-6-nitrospiro-(2H-1-benzopyran-2,2'-(2H)-indoline); D058646:Adrenergic alpha-1 Receptor Agonists; D000873:Anthracenes; D001426:Bacterial Proteins; D001578:Benzopyrans; D002070:Butadienes; D004151:Dipeptides; D005419:Flavonoids; D006877:Hydroxamic Acids; D007093:Imidazoles; C107086:KB R7785; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D009570:Nitriles; D011725:Pyridines; D011799:Quinazolines; D018340:Receptors, Adrenergic, alpha-1; D020032:Tyrphostins; C113580:U 0126; C028581:CRM197 (non-toxic variant of diphtheria toxin); C101044:RTKI cpd; C432165:pyrazolanthrone; D010656:Phenylephrine; D066246:ErbB Receptors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D013917:Thrombin; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D005998:Glycine