PMID- 15486316 OWN - NLM STAT- MEDLINE DCOM- 20050527 LR - 20181201 IS - 1524-4571 (Electronic) IS - 0009-7330 (Linking) VI - 95 IP - 10 DP - 2004 Nov 12 TI - Transactivation of epidermal growth factor receptor mediates catecholamine-induced growth of vascular smooth muscle. PG - 989-97 AB - 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. FAU - Zhang, Hua AU - Zhang H AD - Department of Cell and Molecular Physiology, School of Medicine, University of North Carolina, Chapel Hill, NC 27599-7545, USA. FAU - Chalothorn, Dan AU - Chalothorn D FAU - Jackson, Leslie F AU - Jackson LF FAU - Lee, David C AU - Lee DC FAU - Faber, James E AU - Faber JE LA - eng GR - CA43973/CA/NCI NIH HHS/United States GR - HL62584/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, U.S. Gov't, P.H.S. DEP - 20041014 PL - United States TA - Circ Res JT - Circulation research JID - 0047103 RN - 0 (1',3-dihydro-1'-(2-carboxyethyl)-3,3-dimethyl-6-nitrospiro-(2H-1-benzopyran-2,2'-(2H)-indoline)) RN - 0 (Adrenergic alpha-1 Receptor Agonists) RN - 0 (Anthracenes) RN - 0 (Bacterial Proteins) RN - 0 (Benzopyrans) RN - 0 (Butadienes) RN - 0 (Dipeptides) RN - 0 (Flavonoids) RN - 0 (Hydroxamic Acids) RN - 0 (Imidazoles) RN - 0 (KB R7785) RN - 0 (N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide) RN - 0 (Nitriles) RN - 0 (Pyridines) RN - 0 (Quinazolines) RN - 0 (Receptors, Adrenergic, alpha-1) RN - 0 (Tyrphostins) RN - 0 (U 0126) RN - 08VC9WC084 (CRM197 (non-toxic variant of diphtheria toxin)) RN - 170449-18-0 (RTKI cpd) RN - 1TW30Y2766 (pyrazolanthrone) RN - 1WS297W6MV (Phenylephrine) RN - EC 2.7.10.1 (ErbB Receptors) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3) RN - EC 2.7.12.2 (MAP Kinase Kinase 1) RN - EC 2.7.12.2 (MAP Kinase Kinase 2) RN - EC 3.4.21.5 (Thrombin) RN - OU13V1EYWQ (SB 203580) RN - SJE1IO5E3I (2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one) RN - TE7660XO1C (Glycine) SB - IM MH - Adrenergic alpha-1 Receptor Agonists MH - Animals MH - Anthracenes/pharmacology MH - Aorta, Thoracic/injuries/pathology MH - Bacterial Proteins/pharmacology MH - Benzopyrans/pharmacology MH - Butadienes/pharmacology MH - Catheterization/adverse effects MH - Cell Division MH - Dipeptides/pharmacology MH - ErbB Receptors/drug effects/*physiology MH - Flavonoids/pharmacology MH - Glycine/*analogs & derivatives/pharmacology MH - Hydroxamic Acids/pharmacology MH - Imidazoles/pharmacology MH - MAP Kinase Kinase 1/physiology MH - MAP Kinase Kinase 2/physiology MH - MAP Kinase Signaling System/drug effects/*physiology MH - Mitogen-Activated Protein Kinase 1/physiology MH - Mitogen-Activated Protein Kinase 3/physiology MH - Muscle, Smooth, Vascular/*cytology MH - Myocytes, Smooth Muscle/*cytology/drug effects/enzymology MH - Nitriles/pharmacology MH - Organ Culture Techniques MH - Phenylephrine/pharmacology MH - Phosphorylation/drug effects MH - Protein Processing, Post-Translational/drug effects MH - Pyridines/pharmacology MH - Quinazolines MH - Rats MH - Receptors, Adrenergic, alpha-1/*physiology MH - Thrombin/pharmacology MH - Tyrphostins/pharmacology EDAT- 2004/10/16 09:00 MHDA- 2005/05/28 09:00 CRDT- 2004/10/16 09:00 PHST- 2004/10/16 09:00 [pubmed] PHST- 2005/05/28 09:00 [medline] PHST- 2004/10/16 09:00 [entrez] AID - 01.RES.0000147962.01036.bb [pii] AID - 10.1161/01.RES.0000147962.01036.bb [doi] PST - ppublish SO - Circ Res. 2004 Nov 12;95(10):989-97. doi: 10.1161/01.RES.0000147962.01036.bb. Epub 2004 Oct 14.