Role of epidermal growth factor receptor transactivation in endothelin-1-induced enhanced expression of Gi protein and proliferation in A10 vascular smooth muscle cells

Abstract

We have recently shown that vasoactive peptides such as angiotensin II (Ang II) and endothelin-1 (ET-1) increase the expression of Gi proteins and the proliferation of A10 vascular smooth muscle cells (VSMC) through mitogen-activated protein (MAP) kinase-phosphoinositide (PI) 3-kinase pathways. This study was intended to examine the implication of epidermal growth factor receptor (EGFR) activation in ET-1-induced enhanced expression of Gi proteins and proliferation of A10 VSMC, and to further investigate the underlying mechanisms responsible for these increases. Cell proliferation was determined by [(3)H]thymidine incorporation and the expression of Gi proteins; extracellular signal-regulated kinases 1 and 2 (ERK1/2) and EGFR phosphorylation was determined by Western blotting. Treatment of A10 VSMC with ET-1 enhanced the expression of Gi proteins, which was attenuated by BQ123 and BQ788, antagonists of ET(A) and ET(B) receptor respectively. In addition, ET-1 enhanced the phosphorylation of EGFR in A10 VSMC, which was restored to the control levels by EGFR inhibitor and ETA and ETB receptor antagonists. Furthermore, ET-1 also augmented the proliferation and ERK1/2 phosphorylation of A10 VSMC, which were restored to the control levels by inhibition of EGFR. These data suggest that ET-1 transactivates EGFR, which, through MAP kinase signaling, may contribute to the enhanced expression of Gi proteins and thus increased proliferation of A10 VSMC.

Oxidative stress contributes to the enhanced expression of Gqα/PLCβ1 proteins and hypertrophy of VSMC from SHR: role of growth factor receptor transactivation

“…These results are consistent with our earlier studies showing a role of growth factor receptors in the enhanced expression of Gi␣ proteins and hyperproliferation of VSMCs from SHRs (17,33). In addition, ET-1 was also shown to enhance the expression of Gi␣ proteins and proliferation through the transactivation of EGFR in A 10 VSMC (18). Furthermore, a role of growth factor receptors in VSMC hypertrophy has also been shown by several studies (7,9,10).…”

Sirtuin1 contributes to the overexpression of Giα proteins and hyperproliferation of vascular smooth muscle cells from spontaneously hypertensive rats

“…In the present study, we report for the first time that Sirt1 is overexpressed in aorta and VSMC from SHR and the enhanced expression of Sirt1 in VSMC from SHR contributes to the overexpression of Giα proteins that was shown to be implicated in the pathogenesis of hypertension and vascular remodeling [1,6,36,41]. The role of Sirt1 in Ang II-induced hypertension has been demonstrated in a recent study showing that Ang II-induced high blood pressure in wild type mice was significantly attenuated in Sirt1 knockout mice [28], however, these investigators did not examine if the attenuation of hypertension in Sirt1 knockout mice is attributed to the inhibition of Ang II-induced overexpression of Giα proteins.…”

Insights into cellular signalling by G protein coupled receptor transactivation of cell surface protein kinase receptors

“…The first study describing GPCR mediated transactivation of a PTKR was observed in rat fibroblasts where agonists to endothelin, thrombin and lysophosphatidic acid (LPA) receptor activated the EGFR (Daub et al 1996). Since this primary observation these GPCR agonists have been involved in transactivation of the EGFR in multiple cell models including vascular smooth muscle cells (VSMCs) Burch et al 2010aBurch et al , 2013Kamato et al 2016a;Gomez Sandoval et al 2013), cancer cells (Moody et al 2016;Tveteraas et al 2016) and brain injury model. Since the initial discovery, there have been almost two hundred reports of GPCR transactivation of PTKRs.…”