Consequences of Epidermal Growth Factor Receptor (ErbB1) Loss for Vascular Smooth Muscle Cells From Mice With Targeted Deletion of ErbB1
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 (EGFRΔ/Δ VSMC→VSMCEGFR−/− and EGFRΔ/+ VSMC→VSMCEGFR+/−) and the respective littermate controls (EGFR+/+ VSMC→VSMCEGFR+/+) with respect to survival, pentose phosphate pathway activity, matrix homeostasis, extracellular signal–regulated kinase 1/2 (ERK1/2) phosphorylation, and Ca2+ homeostasis. In VSMCEGFR−/−, epidermal growth factor–induced signaling was abolished; VSMCEGFR+/− 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 VSMCEGFR−/− endothelin-1- or α1-adrenoceptor-induced ERK1/2 phosphorylation and the fraction of Ca2+ responders were significantly reduced, whereas responsive cells showed a significantly stronger Ca2+ signal. Oxidative stress (H2O2) induced ERK1/2 activation in VSMCEGFR+/+ and VSMCEGFR+/− but not in VSMCEGFR−/−. The Ca2+ signal was enhanced in VSMCEGFR−/−, similar to purinergic stimulation by ATP.
Conclusion—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. Ca2+ 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.
- Received November 5, 2010.
- Accepted April 7, 2011.
- © 2011 American Heart Association, Inc.