RGD Reference Report - Transactivation of epidermal growth factor receptor mediates catecholamine-induced growth of vascular smooth muscle. - Rat Genome Database

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

Authors: Zhang, H  Chalothorn, D  Jackson, LF  Lee, DC  Faber, JE 
Citation: Zhang H, etal., Circ Res. 2004 Nov 12;95(10):989-97. Epub 2004 Oct 14.
RGD ID: 1581908
Pubmed: PMID:15486316   (View Abstract at PubMed)
DOI: DOI:10.1161/01.RES.0000147962.01036.bb   (Journal Full-text)

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.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
epidermal growth factor receptor signaling pathway  IMP 1581908; 1581908 RGD 
positive regulation of smooth muscle cell proliferation  IMP 1581908 RGD 

Molecular Function

Molecular Pathway Annotations    Click to see Annotation Detail View

RGD Manual Annotations

Objects Annotated

Genes (Rattus norvegicus)
Egfr  (epidermal growth factor receptor)
Hbegf  (heparin-binding EGF-like growth factor)

Genes (Mus musculus)
Egfr  (epidermal growth factor receptor)
Hbegf  (heparin-binding EGF-like growth factor)

Genes (Homo sapiens)
EGFR  (epidermal growth factor receptor)
HBEGF  (heparin binding EGF like growth factor)


Additional Information