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Consequences of epidermal growth factor receptor (ErbB1) loss for vascular smooth muscle cells from mice with targeted deletion of ErbB1

Item Type:Article
Title:Consequences of epidermal growth factor receptor (ErbB1) loss for vascular smooth muscle cells from mice with targeted deletion of ErbB1
Creators Name:Schreier, B. and Doehler, M. and Rabe, S. and Schneider, B. and Schwerdt, G. and Ruhs, S. and Sibilia, M. and Gotthardt, M. and Gekle, M. and Grossmann, C.
Abstract:OBJECTIVE: Pathophysiological effects of the epidermal growth factor receptor (EGFR or ErbB1) include vascular remodeling. EGFR transactivation is proposed to contribute significantly to heterologous signaling and remodeling in vascular smooth muscle cells (VSMC). METHODS AND RESULTS: We investigated the importance of EGFR in primary VSMC from aorta of mice with targeted deletion of the EGFR (EGFR(Δ/Δ VSMC)→VSMC(EGFR-/-) and EGFR(Δ/+ VSMC)→VSMC(EGFR+/-)) and the respective littermate controls (EGFR(+/+ VSMC)→VSMC(EGFR+/+)) with respect to survival, pentose phosphate pathway activity, matrix homeostasis, extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation, and Ca(2+) homeostasis. In VSMC(EGFR-/-), epidermal growth factor-induced signaling was abolished; VSMC(EGFR+/-) showed an intermediate phenotype. EGFR deletion enhanced spontaneous cell death, reduced pentose phosphate pathway activity, disturbed cellular matrix homeostasis (collagen III and fibronectin), and abolished epidermal growth factor sensitivity. In VSMC(EGFR-/-) endothelin-1- or α(1)-adrenoceptor-induced ERK1/2 phosphorylation and the fraction of Ca(2+) responders were significantly reduced, whereas responsive cells showed a significantly stronger Ca(2+) signal. Oxidative stress (H(2)O(2)) induced ERK1/2 activation in VSMC(EGFR+/+) and VSMC(EGFR+/-) but not in VSMC(EGFR-/-). The Ca(2+) signal was enhanced in VSMC(EGFR-/-), similar to purinergic stimulation by ATP. CONCLUSIONS: In conclusion, EGFR was found to be important for basal VSMC homeostasis and ERK1/2 activation by the tested G-protein-coupled receptors or radical stress. Ca(2+) signaling was modulated by EGFR differentially with respect to the fraction of responders and magnitude of the signal. Thus, EGFR seems to be Janus-faced for VSMC biology.
Keywords:Growth Factors, Receptors, Signal Transduction, Vascular Biology, Vascular Muscle, Animals, Mice
Source:Arteriosclerosis Thrombosis and Vascular Biology
Publisher:American Heart Association
Page Range:1643-1652
Date:July 2011
Official Publication:https://doi.org/10.1161/ATVBAHA.111.223537
PubMed:View item in PubMed

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