title: Substance-specific importance of EGFR for vascular smooth muscle cells motility in primary culture.
abstract: Besides their importance for the vascular tone, vascular smooth muscle cells (VSMC) also contribute to pathophysiological vessel alterations. Various G-protein coupled receptor ligands involved in vascular dysfunction and remodeling can transactivate the epidermal growth factor receptor (EGFR) of VSMC, yet the importance of EGFR transactivation for the VSMC phenotype is incompletely understood. The aims of this study were (i) to characterize further the importance of the VSMC-EGFR for proliferation, migration and marker gene expression for inflammation, fibrosis and reactive oxygen species (ROS) homeostasis and (ii) to test the hypothesis that vasoactive substances (endothelin-1, phenylephrine, thrombin, vasopressin and ATP) rely differentially on the EGFR with respect to the abovementioned phenotypic alterations. In primary, aortic VSMC from mice without conditional deletion of the EGFR, proliferation, migration, marker gene expression (inflammation, fibrosis and ROS homeostasis) and cell signaling (ERK 1/2, intracellular calcium) were analyzed. VSMC-EGFR loss reduced collective cell migration and single cell migration probability, while no difference between the genotypes in single cell velocity, chemotaxis or marker gene expression could be observed under control conditions. EGF promoted proliferation, collective cell migration, chemokinesis and chemotaxis and leads to a proinflammatory gene expression profile in wildtype but not in knockout VSMC. Comparing the impact of five vasoactive substances (all reported to transactivate EGFR and all leading to an EGFR dependent increase in ERK1/2 phosphorylation), we demonstrate that the importance of EGFR for their action is substance-dependent and most apparent for crowd migration but plays a minor role for gene expression regulation.
authors.affiliation: Julius-Bernstein-Institute of Physiology, University of Halle-Wittenberg, Magdeburger Strasse 6, 06112 Halle/Saale, Germany. Electronic address: barbara.schreier@medizin.uni-halle.de.
authors.forename: Barbara
authors.initials: B
authors.lastname: Schreier
authors.affiliation: Julius-Bernstein-Institute of Physiology, University of Halle-Wittenberg, Magdeburger Strasse 6, 06112 Halle/Saale, Germany.
authors.forename: Gerald
authors.initials: G
authors.lastname: Schwerdt
authors.affiliation: Julius-Bernstein-Institute of Physiology, University of Halle-Wittenberg, Magdeburger Strasse 6, 06112 Halle/Saale, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Heise
authors.affiliation: Julius-Bernstein-Institute of Physiology, University of Halle-Wittenberg, Magdeburger Strasse 6, 06112 Halle/Saale, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Bethmann
authors.affiliation: Julius-Bernstein-Institute of Physiology, University of Halle-Wittenberg, Magdeburger Strasse 6, 06112 Halle/Saale, Germany.
authors.forename: Sindy
authors.initials: S
authors.lastname: Rabe
authors.affiliation: Julius-Bernstein-Institute of Physiology, University of Halle-Wittenberg, Magdeburger Strasse 6, 06112 Halle/Saale, Germany.
authors.forename: Sigrid
authors.initials: S
authors.lastname: Mildenberger
authors.affiliation: Julius-Bernstein-Institute of Physiology, University of Halle-Wittenberg, Magdeburger Strasse 6, 06112 Halle/Saale, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Gekle
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000494:pharmacology; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000819:agonists / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005355:Fibrosis; D005786:Gene Expression Regulation; D005838:Genotype; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology*; D018384:Oxidative Stress; D010641:Phenotype; D010656:Phenylephrine / Q000494:pharmacology; D061251:Primary Cell Culture; D015398:Signal Transduction; D013917:Thrombin / Q000494:pharmacology; D013997:Time Factors; D014667:Vasopressins / Q000494:pharmacology
chemical_list: D019332:Endothelin-1; D008024:Ligands; D014667:Vasopressins; D010656:Phenylephrine; D004815:Epidermal Growth Factor; D000255:Adenosine Triphosphate; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D013917:Thrombin
keywords: Epidermal growth factor receptor; Gene expression; Migration; Proliferation; Transactivation; Vascular smooth muscle cells