title: Consequences of postnatal vascular smooth muscle EGFR deletion on acute angiotensin II action.
abstract: Epi dermal growth factor (EGF) receptor (EGFR) is activated by its canonical ligands and transactivated by various vasoactive substances, e.g. angiotensin II (Ang II). Vascular EGFR has been proposed to be involved in vascular tissue homoeostasis and remodelling. Thus, most studies have focused on its role during long-term vascular changes whereas the relevance for acute regulation of vascular function in vivo and ex vivo is insufficiently understood. To investigate the postnatal role of VSMCs (vascular smooth muscle cells) EGFR in vivo and ex vivo, we generated a mouse model with cell-specific and inducible deletion of VSMC EGFR and studied the effect on basal blood pressure, acute pressure response to, among others, Ang II in vivo as well as ex vivo, cardiovascular tissue homoeostasis and vessel morphometry in male mice. In knockout (KO) animals, systolic, diastolic and mean blood pressures were reduced compared with wild-type (WT). Furthermore, Ang II-induced pressure load was lower in KO animals, as was Ang II-induced force development and extracellular-signal-regulated kinase 1 and 2 (ERK1/2) phosphorylation in aortic rings from KO animals. By contrast, we observed no difference in force development during application of serotonin, KCl, endothelin-1 or endothelin-1-induced pressure load in KO animals. In addition, nitric oxide (NO)-mediated vasodilation was not affected. Heart weight (HW) increase and up-regulation of aortic and cardiac expression of Ccl2 (chemoattractant protein-2) and serpinE1 (plasminogen activator inhibitor 1) during the transition from 4- to 10-months of age were prevented by VSMC EGFR KO. We conclude that VSMC EGFR is involved in basal blood pressure homoeostasis and acute pressure response to Ang II, and thereby contributes to maturation-related remodelling.
authors.affiliation: Julius-Bernstein-Institute of Physiology, Martin Luther University Halle-Wittenberg, 06112 Halle, Germany barbara.schreier@medizin.uni-halle.de.
authors.forename: Barbara
authors.initials: B
authors.lastname: Schreier
authors.affiliation: Julius-Bernstein-Institute of Physiology, Martin Luther University Halle-Wittenberg, 06112 Halle, Germany.
authors.forename: Mirja
authors.initials: M
authors.lastname: Hünerberg
authors.affiliation: Julius-Bernstein-Institute of Physiology, Martin Luther University Halle-Wittenberg, 06112 Halle, Germany.
authors.forename: Sindy
authors.initials: S
authors.lastname: Rabe
authors.affiliation: Julius-Bernstein-Institute of Physiology, Martin Luther University Halle-Wittenberg, 06112 Halle, Germany.
authors.forename: Sigrid
authors.initials: S
authors.lastname: Mildenberger
authors.affiliation: Julius-Bernstein-Institute of Physiology, Martin Luther University Halle-Wittenberg, 06112 Halle, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Bethmann
authors.affiliation: Julius-Bernstein-Institute of Physiology, Martin Luther University Halle-Wittenberg, 06112 Halle, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Heise
authors.affiliation: Institute of Cancer Research, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Maria
authors.initials: M
authors.lastname: Sibilia
authors.affiliation: Department of Pharmacology, Max-Planck-Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Offermanns
authors.affiliation: Julius-Bernstein-Institute of Physiology, Martin Luther University Halle-Wittenberg, 06112 Halle, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Gekle
mesh_terms: D000367:Age Factors; D000804:Angiotensin II; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D006332:Cardiomegaly / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D018932:Chemokine CCL2 / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000172:deficiency* / Q000235:genetics; D017353:Gene Deletion; D006801:Humans; D006973:Hypertension / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control; 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* / Q000503:physiopathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D066253:Vascular Remodeling; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D017395:Plasminogen Activator Inhibitor 1; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; C541485:EGFR protein, mouse; D066246:ErbB Receptors; C535148:Mapk1 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
keywords: angiotensin II; endothelin-1; epidermal growth factor receptor; hypotension; mouse model; vascular smooth muscle cells