title: Consequences of epidermal growth factor receptor (ErbB1) loss for vascular smooth muscle cells from mice with targeted deletion of ErbB1.
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).
  
  
  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.
authors.affiliation: Julius-Bernstein-Institute of Physiology, University of Halle-Wittenberg, Halle, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Schreier
authors.forename: Maria
authors.initials: M
authors.lastname: Döhler
authors.forename: Sindy
authors.initials: S
authors.lastname: Rabe
authors.forename: Bettina
authors.initials: B
authors.lastname: Schneider
authors.forename: Gerald
authors.initials: G
authors.lastname: Schwerdt
authors.forename: Stefanie
authors.initials: S
authors.lastname: Ruhs
authors.forename: Maria
authors.initials: M
authors.lastname: Sibilia
authors.forename: Michael
authors.initials: M
authors.lastname: Gotthardt
authors.forename: Michael
authors.initials: M
authors.lastname: Gekle
authors.forename: Claudia
authors.initials: C
authors.lastname: Grossmann
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D058646:Adrenergic alpha-1 Receptor Agonists / Q000494:pharmacology; D000818:Animals; D020013:Calcium Signaling; D002470:Cell Survival; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000378:metabolism; D066246:ErbB Receptors / Q000172:deficiency* / Q000187:drug effects / Q000235:genetics; D005109:Extracellular Matrix / Q000378:metabolism; D005838:Genotype; D006706:Homeostasis; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress; D010427:Pentose Phosphate Pathway; D010641:Phenotype; D010656:Phenylephrine / Q000494:pharmacology; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013997:Time Factors
chemical_list: D058646:Adrenergic alpha-1 Receptor Agonists; D019332:Endothelin-1; D016877:Oxidants; D012333:RNA, Messenger; D010656:Phenylephrine; D000255:Adenosine Triphosphate; D006861:Hydrogen Peroxide; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3