title: Smooth Muscle Endothelin B Receptors Regulate Blood Pressure but Not Vascular Function or Neointimal Remodeling.
abstract: The role of smooth muscle endothelinB(ETB) receptors in regulating vascular function, blood pressure (BP), and neointimal remodeling has not been established. Selective knockout mice were generated to address the hypothesis that loss of smooth muscle ETBreceptors would reduce BP, alter vascular contractility, and inhibit neointimal remodeling. ETBreceptors were selectively deleted from smooth muscle by crossing floxed ETBmice with those expressing cre-recombinase controlled by the transgelin promoter. Functional consequences of ETBdeletion were assessed using myography. BP was measured by telemetry, and neointimal lesion formation induced by femoral artery injury. Lesion size and composition (day 28) were analyzed using optical projection tomography, histology, and immunohistochemistry. Selective deletion of ETBwas confirmed by genotyping, autoradiography, polymerase chain reaction, and immunohistochemistry. ETB-mediated contraction was reduced in trachea, but abolished from mesenteric veins, of knockout mice. Induction of ETB-mediated contraction in mesenteric arteries was also abolished in these mice. Femoral artery function was unaltered, and baseline BP modestly elevated in smooth muscle ETBknockout compared with controls (+4.2±0.2 mm Hg; P<0.0001), but salt-induced and ETBblockade-mediated hypertension were unaltered. Circulating endothelin-1 was not altered in knockout mice. ETB-mediated contraction was not induced in femoral arteries by incubation in culture medium or lesion formation, and lesion size was not altered in smooth muscle ETBknockout mice. In the absence of other pathology, ETBreceptors in vascular smooth muscle make a small but significant contribution to ETB-dependent regulation of BP. These ETBreceptors have no effect on vascular contraction or neointimal remodeling.
authors.affiliation: From the University/BHF Centre for Cardiovascular Science, University of Edinburgh, United Kingdom (E.M., A.C., K.M.D., N.S.K., E.E.F.v.d.P., R.A.K., R.M., R.F.P.C., N.D., D.J.W., P.W.F.H.); University of Basel, Switzerland (S.C.); Centre for Functional Genomics, Skolkovo Institute of Science and Technology, Russian Federation (Y.V.K.); and Division of Experimental Medicine and Immunotherapeutics, Addenbrooke's Hospital, Cambridge, United Kingdom (R.E.K., A.P.D.).
authors.forename: Eileen
authors.initials: E
authors.lastname: Miller
authors.affiliation: From the University/BHF Centre for Cardiovascular Science, University of Edinburgh, United Kingdom (E.M., A.C., K.M.D., N.S.K., E.E.F.v.d.P., R.A.K., R.M., R.F.P.C., N.D., D.J.W., P.W.F.H.); University of Basel, Switzerland (S.C.); Centre for Functional Genomics, Skolkovo Institute of Science and Technology, Russian Federation (Y.V.K.); and Division of Experimental Medicine and Immunotherapeutics, Addenbrooke's Hospital, Cambridge, United Kingdom (R.E.K., A.P.D.).
authors.forename: Alicja
authors.initials: A
authors.lastname: Czopek
authors.affiliation: From the University/BHF Centre for Cardiovascular Science, University of Edinburgh, United Kingdom (E.M., A.C., K.M.D., N.S.K., E.E.F.v.d.P., R.A.K., R.M., R.F.P.C., N.D., D.J.W., P.W.F.H.); University of Basel, Switzerland (S.C.); Centre for Functional Genomics, Skolkovo Institute of Science and Technology, Russian Federation (Y.V.K.); and Division of Experimental Medicine and Immunotherapeutics, Addenbrooke's Hospital, Cambridge, United Kingdom (R.E.K., A.P.D.).
authors.forename: Karolina M
authors.initials: KM
authors.lastname: Duthie
authors.affiliation: From the University/BHF Centre for Cardiovascular Science, University of Edinburgh, United Kingdom (E.M., A.C., K.M.D., N.S.K., E.E.F.v.d.P., R.A.K., R.M., R.F.P.C., N.D., D.J.W., P.W.F.H.); University of Basel, Switzerland (S.C.); Centre for Functional Genomics, Skolkovo Institute of Science and Technology, Russian Federation (Y.V.K.); and Division of Experimental Medicine and Immunotherapeutics, Addenbrooke's Hospital, Cambridge, United Kingdom (R.E.K., A.P.D.).
authors.forename: Nicholas S
authors.initials: NS
authors.lastname: Kirkby
authors.affiliation: From the University/BHF Centre for Cardiovascular Science, University of Edinburgh, United Kingdom (E.M., A.C., K.M.D., N.S.K., E.E.F.v.d.P., R.A.K., R.M., R.F.P.C., N.D., D.J.W., P.W.F.H.); University of Basel, Switzerland (S.C.); Centre for Functional Genomics, Skolkovo Institute of Science and Technology, Russian Federation (Y.V.K.); and Division of Experimental Medicine and Immunotherapeutics, Addenbrooke's Hospital, Cambridge, United Kingdom (R.E.K., A.P.D.).
authors.forename: Elisabeth E Fransen
authors.initials: EE
authors.lastname: van de Putte
authors.affiliation: From the University/BHF Centre for Cardiovascular Science, University of Edinburgh, United Kingdom (E.M., A.C., K.M.D., N.S.K., E.E.F.v.d.P., R.A.K., R.M., R.F.P.C., N.D., D.J.W., P.W.F.H.); University of Basel, Switzerland (S.C.); Centre for Functional Genomics, Skolkovo Institute of Science and Technology, Russian Federation (Y.V.K.); and Division of Experimental Medicine and Immunotherapeutics, Addenbrooke's Hospital, Cambridge, United Kingdom (R.E.K., A.P.D.).
authors.forename: Sibylle
authors.initials: S
authors.lastname: Christen
authors.affiliation: From the University/BHF Centre for Cardiovascular Science, University of Edinburgh, United Kingdom (E.M., A.C., K.M.D., N.S.K., E.E.F.v.d.P., R.A.K., R.M., R.F.P.C., N.D., D.J.W., P.W.F.H.); University of Basel, Switzerland (S.C.); Centre for Functional Genomics, Skolkovo Institute of Science and Technology, Russian Federation (Y.V.K.); and Division of Experimental Medicine and Immunotherapeutics, Addenbrooke's Hospital, Cambridge, United Kingdom (R.E.K., A.P.D.).
authors.forename: Robert A
authors.initials: RA
authors.lastname: Kimmitt
authors.affiliation: From the University/BHF Centre for Cardiovascular Science, University of Edinburgh, United Kingdom (E.M., A.C., K.M.D., N.S.K., E.E.F.v.d.P., R.A.K., R.M., R.F.P.C., N.D., D.J.W., P.W.F.H.); University of Basel, Switzerland (S.C.); Centre for Functional Genomics, Skolkovo Institute of Science and Technology, Russian Federation (Y.V.K.); and Division of Experimental Medicine and Immunotherapeutics, Addenbrooke's Hospital, Cambridge, United Kingdom (R.E.K., A.P.D.).
authors.forename: Rebecca
authors.initials: R
authors.lastname: Moorhouse
authors.affiliation: From the University/BHF Centre for Cardiovascular Science, University of Edinburgh, United Kingdom (E.M., A.C., K.M.D., N.S.K., E.E.F.v.d.P., R.A.K., R.M., R.F.P.C., N.D., D.J.W., P.W.F.H.); University of Basel, Switzerland (S.C.); Centre for Functional Genomics, Skolkovo Institute of Science and Technology, Russian Federation (Y.V.K.); and Division of Experimental Medicine and Immunotherapeutics, Addenbrooke's Hospital, Cambridge, United Kingdom (R.E.K., A.P.D.).
authors.forename: Raphael F P
authors.initials: RF
authors.lastname: Castellan
authors.affiliation: From the University/BHF Centre for Cardiovascular Science, University of Edinburgh, United Kingdom (E.M., A.C., K.M.D., N.S.K., E.E.F.v.d.P., R.A.K., R.M., R.F.P.C., N.D., D.J.W., P.W.F.H.); University of Basel, Switzerland (S.C.); Centre for Functional Genomics, Skolkovo Institute of Science and Technology, Russian Federation (Y.V.K.); and Division of Experimental Medicine and Immunotherapeutics, Addenbrooke's Hospital, Cambridge, United Kingdom (R.E.K., A.P.D.).
authors.forename: Yuri V
authors.initials: YV
authors.lastname: Kotelevtsev
authors.affiliation: From the University/BHF Centre for Cardiovascular Science, University of Edinburgh, United Kingdom (E.M., A.C., K.M.D., N.S.K., E.E.F.v.d.P., R.A.K., R.M., R.F.P.C., N.D., D.J.W., P.W.F.H.); University of Basel, Switzerland (S.C.); Centre for Functional Genomics, Skolkovo Institute of Science and Technology, Russian Federation (Y.V.K.); and Division of Experimental Medicine and Immunotherapeutics, Addenbrooke's Hospital, Cambridge, United Kingdom (R.E.K., A.P.D.).
authors.forename: Rhoda E
authors.initials: RE
authors.lastname: Kuc
authors.affiliation: From the University/BHF Centre for Cardiovascular Science, University of Edinburgh, United Kingdom (E.M., A.C., K.M.D., N.S.K., E.E.F.v.d.P., R.A.K., R.M., R.F.P.C., N.D., D.J.W., P.W.F.H.); University of Basel, Switzerland (S.C.); Centre for Functional Genomics, Skolkovo Institute of Science and Technology, Russian Federation (Y.V.K.); and Division of Experimental Medicine and Immunotherapeutics, Addenbrooke's Hospital, Cambridge, United Kingdom (R.E.K., A.P.D.).
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Davenport
authors.affiliation: From the University/BHF Centre for Cardiovascular Science, University of Edinburgh, United Kingdom (E.M., A.C., K.M.D., N.S.K., E.E.F.v.d.P., R.A.K., R.M., R.F.P.C., N.D., D.J.W., P.W.F.H.); University of Basel, Switzerland (S.C.); Centre for Functional Genomics, Skolkovo Institute of Science and Technology, Russian Federation (Y.V.K.); and Division of Experimental Medicine and Immunotherapeutics, Addenbrooke's Hospital, Cambridge, United Kingdom (R.E.K., A.P.D.).
authors.forename: Neeraj
authors.initials: N
authors.lastname: Dhaun
authors.affiliation: From the University/BHF Centre for Cardiovascular Science, University of Edinburgh, United Kingdom (E.M., A.C., K.M.D., N.S.K., E.E.F.v.d.P., R.A.K., R.M., R.F.P.C., N.D., D.J.W., P.W.F.H.); University of Basel, Switzerland (S.C.); Centre for Functional Genomics, Skolkovo Institute of Science and Technology, Russian Federation (Y.V.K.); and Division of Experimental Medicine and Immunotherapeutics, Addenbrooke's Hospital, Cambridge, United Kingdom (R.E.K., A.P.D.).
authors.forename: David J
authors.initials: DJ
authors.lastname: Webb
authors.affiliation: From the University/BHF Centre for Cardiovascular Science, University of Edinburgh, United Kingdom (E.M., A.C., K.M.D., N.S.K., E.E.F.v.d.P., R.A.K., R.M., R.F.P.C., N.D., D.J.W., P.W.F.H.); University of Basel, Switzerland (S.C.); Centre for Functional Genomics, Skolkovo Institute of Science and Technology, Russian Federation (Y.V.K.); and Division of Experimental Medicine and Immunotherapeutics, Addenbrooke's Hospital, Cambridge, United Kingdom (R.E.K., A.P.D.). Patrick.Hadoke@ed.ac.uk.
authors.forename: Patrick W F
authors.initials: PW
authors.lastname: Hadoke
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006973:Hypertension / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D058426:Neointima; D012313:RNA / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D044023:Receptor, Endothelin B / Q000096:biosynthesis / Q000235:genetics*; D066253:Vascular Remodeling; D014661:Vasoconstriction / Q000502:physiology*
chemical_list: D044023:Receptor, Endothelin B; D012313:RNA
keywords: autoradiography; endothelin-1; hypertension; neointima; vasoconstriction