α₁‐Adrenoceptor‐mediated contraction of rat aorta is partly mediated via transactivation of the epidermal growth factor receptor

Abstract

Background and purpose: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 a1-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 a1-adrenoceptors. Experimental approach: 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. Key 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 and implications:Contractions of rat thoracic aorta mediated by a1-adrenoceptors involved transactivation of EGFR, mediated via a PI3K and ERK1/2 dependent pathway.

Enhanced p22phoxexpression impairs vascular function through p38 and ERK1/2 MAP kinase-dependent mechanisms in type 2 diabetic mice

“…Nevertheless, our results are in accordance with previous studies in which ERK inhibition reduced PE-induced contractions in MRAs from diabetic mice (28). However, these results are still not clear since a previous study showed that ERK1/2 inhibition did not affect PE-induced contraction in aorta from rats (47). These results suggest that the role of ERK1/2 in ␣ 1 -adenoreceptor-mediated contraction shows considerable heterogeneity depending on vessel types.…”

Intracellular Transactivation of Epidermal Growth Factor Receptor byα1A-Adrenoceptor Is Mediated by Phosphatidylinositol 3-Kinase Independently of Activation of Extracellular Signal Regulated Kinases 1/2 and Serine-Threonine Kinases in Chinese Hamster Ovary Cells

“…We recently had demonstrated that a 1 -AR induced transactivation of EGFR contributes to VSMC contraction in rat aorta (i.e., to immediate affect the a 1 -AR response) (Ulu et al, 2010), so we first explored whether a similar transactivation occurs in serum-starved cultured A7R5 VSMCs, which express all three a 1 -ARs (data not shown). Stimulation of a 1 -AR by 10 mM PE and EGFR by 1 nM EGF induced phosphorylation of EGFR in A7R5 VSMCs.…”

“…In that study, a 1 -AR stimulation resulted in EGFR phosphorylation in rat aorta, while the EGFR kinase inhibitors AG1478 [4-(39-chloroanilino)-6,7-dimethoxyquinazoline] and DAPH (4,5-dianilinophthalimide) concentration-dependently attenuated phenylephrine (PE)-induced contractile responses (Ulu et al, 2010). Moreover, in our recent study, EGFR kinase inhibitor …”

“…However, in our recent study in rat aorta, we observed a 1 -AR-mediated transactivation of EGFR to be independent from MMPs, which suggests that it depends on an intracellular route (Ulu et al, 2010). Therefore, in this study, we address whether an intracellular or extracellular signaling route is involved in the transactivation of EGFR by examining a 1A -AR-induced phosphorylation of a chimeric erythropoietin receptor (EPOR)/EGFR in Chinese hamster ovary (CHO) cells.…”

Epidermal Growth Factor Receptor Inhibitor PKI-166 Governs Cardiovascular Protection without Beneficial Effects on the Kidney in Hypertensive 5/6 Nephrectomized Rats

“…For example, in heart failure, increased myogenic constriction of mesenteric artery is due to AT 1 R-mediated transactivation of EGFR (Xu et al, 2009). Moreover, we recently showed that transactivation of the EGFR governs part of the a 1 -AR-induced contraction of rat aorta (Ulu et al, 2010). A potential mechanism involved in EGFR transactivation is GPCRinduced shedding of heparin-binding EGF-like growth factor, which subsequently activates EGFR (Asakura et al, 2002).…”