α1-Adrenoceptor-mediated contraction of rat aorta is partly mediated via transactivation of the epidermal growth factor receptor.
OBJECTIVE
High level of plasma catecholamines is a risk factor for vascular diseases such as hypertension and atherosclerosis. Catecholamines induce hypertrophy of vascular smooth muscle through α(1) -adrenoceptors, which in cell culture involves the transactivation of epidermal growth factor receptor (EGFR). We hypothesized that EGFR transactivation was also involved in contractions of rat aorta mediated by α(1) -adrenoceptors.


METHODS
Thoracic aorta was isolated from 12-14 week old male Wistar rats. In vitro aortic contractile responses to cumulative doses of phenylephrine were characterized in the absence and presence of the EGFR kinase inhibitors, AG1478 and DAPH, in intact and endothelium-denuded rings. Involvement of signal transduction pathways was investigated by using heparin and inhibitors of Src, matrix metalloproteinase (MMP), extracellular signal-regulated kinase (ERK)1/2 and phosphatidyl inositol 3-kinase (PI3K). Phosphorylation of EGFR and ERK1/2 was measured after short-term phenylephrine or EGF stimulation in aorta segments in the presence of AG1478 and the PI3K inhibitor, wortmannin.


RESULTS
AG1478 and DAPH concentration dependently attenuated phenylephrine-induced contractile responses in intact or endothelium-denuded aortic rings. Inhibition of PI3K (wortmannin and LY294002) but not heparin or inhibitors of Src or MMP, prevented the effect of AG1478 on the responses to phenylephrine. Phenylephrine induced phosphorylation of EGFR, which was partially blocked by AG1478. Phenylephrine also increased phosphorylation of ERK1/2, time-dependently and was blocked by AG1478 and wortmannin.


CONCLUSIONS
Contractions of rat thoracic aorta mediated by α(1) -adrenoceptors involved transactivation of EGFR, mediated via a PI3K and ERK1/2 dependent pathway.
Department of Clinical Pharmacology, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands. n.ulu@med.umcg.nl
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Ulu
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Gurdal
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Landheer
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Duin
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Guc
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Buikema
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RH
Henning
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D011799:Quinazolines; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D018340:Receptors, Adrenergic, alpha-1 / Q000502:physiology*; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology*; D020032:Tyrphostins / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*
C547715:Adra1a protein, rat; D011799:Quinazolines; D018340:Receptors, Adrenergic, alpha-1; D020032:Tyrphostins; C101044:RTKI cpd; D066246:ErbB Receptors