title: Class IA Phosphatidylinositol 3-Kinase Isoform p110α Mediates Vascular Remodeling.
abstract: OBJECTIVE
  Neointima formation after vascular injury remains a significant problem in clinical cardiology, and current preventive strategies are suboptimal. Phosphatidylinositol 3'-kinase is a central downstream mediator of growth factor signaling, but the role of phosphatidylinositol 3'-kinase isoforms in vascular remodeling remains elusive. We sought to systematically characterize the precise role of catalytic class IA phosphatidylinositol 3'-kinase isoforms (p110α, p110β, p110δ), which signal downstream of receptor tyrosine kinases, for vascular remodeling in vivo.
  
  
  RESULTS
  Western blot analyses revealed that all 3 isoforms are abundantly expressed in smooth muscle cells. To analyze their significance for receptor tyrosine kinases-dependent cellular responses, we used targeted gene knockdown and isoform-specific small molecule inhibitors of p110α (PIK-75), p110β (TGX-221), and p110δ (IC-87114), respectively. We identified p110α to be crucial for receptor tyrosine kinases signaling, thus affecting proliferation, migration, and survival of rat, murine, and human smooth muscle cells, whereas p110β and p110δ activities were dispensable. Surprisingly, p110δ exerted noncatalytic functions in smooth muscle cell proliferation, but had no effect on migration. Based on these results, we generated a mouse model of smooth muscle cell-specific p110α deficiency (sm-p110α(-/-)). Targeted deletion of p110α in sm-p110α(-/-) mice blunted growth factor-induced cellular responses and abolished neointima formation after balloon injury of the carotid artery in mice. In contrast, p110δ deficiency did not affect vascular remodeling in vivo.
  
  
  CONCLUSIONS
  Receptor tyrosine kinases-induced phosphatidylinositol 3'-kinase signaling via the p110α isoform plays a central role for vascular remodeling in vivo. Thus, p110α represents a selective target for the prevention of neointima formation after vascular injury, whereas p110β and p110δ expression and activity do not play a significant role.
authors.affiliation: From the Klinik III für Innere Medizin, Universität zu Köln, Germany (M.V., J.J., E.M.B., L.M., X.C., T.K., M.Z., M.G., H.t.F., S.B., S.R.); Center for Molecular Medicine Cologne (CMMC), Universität zu Köln, Germany (M.V., J.J., E.M.B., L.M., X.C., T.K., M.Z., M.G., H.t.F., S.B., S.R.); Center for R&D, Uppsala University/County Council of Gävleborg, Gävle, Sweden (O.L.); Klinik für Herz- und Thoraxchirurgie, Universität zu Köln, Germany (M.S.); Cologne Cardiovascular Research Center (CCRC), Universität zu Köln, Germany (H.t.F., S.B., S.R.); Klinik für Kardiologie, Charité Universitätsmedizin, Berlin, Germany (F.B.); Institut für Experimentelle Medizin, Universität zu Köln, Germany (A.S.-K.); and Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA (J.J.Z.).
authors.forename: Marius
authors.initials: M
authors.lastname: Vantler
authors.affiliation: From the Klinik III für Innere Medizin, Universität zu Köln, Germany (M.V., J.J., E.M.B., L.M., X.C., T.K., M.Z., M.G., H.t.F., S.B., S.R.); Center for Molecular Medicine Cologne (CMMC), Universität zu Köln, Germany (M.V., J.J., E.M.B., L.M., X.C., T.K., M.Z., M.G., H.t.F., S.B., S.R.); Center for R&D, Uppsala University/County Council of Gävleborg, Gävle, Sweden (O.L.); Klinik für Herz- und Thoraxchirurgie, Universität zu Köln, Germany (M.S.); Cologne Cardiovascular Research Center (CCRC), Universität zu Köln, Germany (H.t.F., S.B., S.R.); Klinik für Kardiologie, Charité Universitätsmedizin, Berlin, Germany (F.B.); Institut für Experimentelle Medizin, Universität zu Köln, Germany (A.S.-K.); and Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA (J.J.Z.).
authors.forename: Joana
authors.initials: J
authors.lastname: Jesus
authors.affiliation: From the Klinik III für Innere Medizin, Universität zu Köln, Germany (M.V., J.J., E.M.B., L.M., X.C., T.K., M.Z., M.G., H.t.F., S.B., S.R.); Center for Molecular Medicine Cologne (CMMC), Universität zu Köln, Germany (M.V., J.J., E.M.B., L.M., X.C., T.K., M.Z., M.G., H.t.F., S.B., S.R.); Center for R&D, Uppsala University/County Council of Gävleborg, Gävle, Sweden (O.L.); Klinik für Herz- und Thoraxchirurgie, Universität zu Köln, Germany (M.S.); Cologne Cardiovascular Research Center (CCRC), Universität zu Köln, Germany (H.t.F., S.B., S.R.); Klinik für Kardiologie, Charité Universitätsmedizin, Berlin, Germany (F.B.); Institut für Experimentelle Medizin, Universität zu Köln, Germany (A.S.-K.); and Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA (J.J.Z.).
authors.forename: Olli
authors.initials: O
authors.lastname: Leppänen
authors.affiliation: From the Klinik III für Innere Medizin, Universität zu Köln, Germany (M.V., J.J., E.M.B., L.M., X.C., T.K., M.Z., M.G., H.t.F., S.B., S.R.); Center for Molecular Medicine Cologne (CMMC), Universität zu Köln, Germany (M.V., J.J., E.M.B., L.M., X.C., T.K., M.Z., M.G., H.t.F., S.B., S.R.); Center for R&D, Uppsala University/County Council of Gävleborg, Gävle, Sweden (O.L.); Klinik für Herz- und Thoraxchirurgie, Universität zu Köln, Germany (M.S.); Cologne Cardiovascular Research Center (CCRC), Universität zu Köln, Germany (H.t.F., S.B., S.R.); Klinik für Kardiologie, Charité Universitätsmedizin, Berlin, Germany (F.B.); Institut für Experimentelle Medizin, Universität zu Köln, Germany (A.S.-K.); and Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA (J.J.Z.).
authors.forename: Maximilian
authors.initials: M
authors.lastname: Scherner
authors.affiliation: From the Klinik III für Innere Medizin, Universität zu Köln, Germany (M.V., J.J., E.M.B., L.M., X.C., T.K., M.Z., M.G., H.t.F., S.B., S.R.); Center for Molecular Medicine Cologne (CMMC), Universität zu Köln, Germany (M.V., J.J., E.M.B., L.M., X.C., T.K., M.Z., M.G., H.t.F., S.B., S.R.); Center for R&D, Uppsala University/County Council of Gävleborg, Gävle, Sweden (O.L.); Klinik für Herz- und Thoraxchirurgie, Universität zu Köln, Germany (M.S.); Cologne Cardiovascular Research Center (CCRC), Universität zu Köln, Germany (H.t.F., S.B., S.R.); Klinik für Kardiologie, Charité Universitätsmedizin, Berlin, Germany (F.B.); Institut für Experimentelle Medizin, Universität zu Köln, Germany (A.S.-K.); and Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA (J.J.Z.).
authors.forename: Eva Maria
authors.initials: EM
authors.lastname: Berghausen
authors.affiliation: From the Klinik III für Innere Medizin, Universität zu Köln, Germany (M.V., J.J., E.M.B., L.M., X.C., T.K., M.Z., M.G., H.t.F., S.B., S.R.); Center for Molecular Medicine Cologne (CMMC), Universität zu Köln, Germany (M.V., J.J., E.M.B., L.M., X.C., T.K., M.Z., M.G., H.t.F., S.B., S.R.); Center for R&D, Uppsala University/County Council of Gävleborg, Gävle, Sweden (O.L.); Klinik für Herz- und Thoraxchirurgie, Universität zu Köln, Germany (M.S.); Cologne Cardiovascular Research Center (CCRC), Universität zu Köln, Germany (H.t.F., S.B., S.R.); Klinik für Kardiologie, Charité Universitätsmedizin, Berlin, Germany (F.B.); Institut für Experimentelle Medizin, Universität zu Köln, Germany (A.S.-K.); and Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA (J.J.Z.).
authors.forename: Lenard
authors.initials: L
authors.lastname: Mustafov
authors.affiliation: From the Klinik III für Innere Medizin, Universität zu Köln, Germany (M.V., J.J., E.M.B., L.M., X.C., T.K., M.Z., M.G., H.t.F., S.B., S.R.); Center for Molecular Medicine Cologne (CMMC), Universität zu Köln, Germany (M.V., J.J., E.M.B., L.M., X.C., T.K., M.Z., M.G., H.t.F., S.B., S.R.); Center for R&D, Uppsala University/County Council of Gävleborg, Gävle, Sweden (O.L.); Klinik für Herz- und Thoraxchirurgie, Universität zu Köln, Germany (M.S.); Cologne Cardiovascular Research Center (CCRC), Universität zu Köln, Germany (H.t.F., S.B., S.R.); Klinik für Kardiologie, Charité Universitätsmedizin, Berlin, Germany (F.B.); Institut für Experimentelle Medizin, Universität zu Köln, Germany (A.S.-K.); and Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA (J.J.Z.).
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.affiliation: From the Klinik III für Innere Medizin, Universität zu Köln, Germany (M.V., J.J., E.M.B., L.M., X.C., T.K., M.Z., M.G., H.t.F., S.B., S.R.); Center for Molecular Medicine Cologne (CMMC), Universität zu Köln, Germany (M.V., J.J., E.M.B., L.M., X.C., T.K., M.Z., M.G., H.t.F., S.B., S.R.); Center for R&D, Uppsala University/County Council of Gävleborg, Gävle, Sweden (O.L.); Klinik für Herz- und Thoraxchirurgie, Universität zu Köln, Germany (M.S.); Cologne Cardiovascular Research Center (CCRC), Universität zu Köln, Germany (H.t.F., S.B., S.R.); Klinik für Kardiologie, Charité Universitätsmedizin, Berlin, Germany (F.B.); Institut für Experimentelle Medizin, Universität zu Köln, Germany (A.S.-K.); and Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA (J.J.Z.).
authors.forename: Tilmann
authors.initials: T
authors.lastname: Kramer
authors.affiliation: From the Klinik III für Innere Medizin, Universität zu Köln, Germany (M.V., J.J., E.M.B., L.M., X.C., T.K., M.Z., M.G., H.t.F., S.B., S.R.); Center for Molecular Medicine Cologne (CMMC), Universität zu Köln, Germany (M.V., J.J., E.M.B., L.M., X.C., T.K., M.Z., M.G., H.t.F., S.B., S.R.); Center for R&D, Uppsala University/County Council of Gävleborg, Gävle, Sweden (O.L.); Klinik für Herz- und Thoraxchirurgie, Universität zu Köln, Germany (M.S.); Cologne Cardiovascular Research Center (CCRC), Universität zu Köln, Germany (H.t.F., S.B., S.R.); Klinik für Kardiologie, Charité Universitätsmedizin, Berlin, Germany (F.B.); Institut für Experimentelle Medizin, Universität zu Köln, Germany (A.S.-K.); and Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA (J.J.Z.).
authors.forename: Mario
authors.initials: M
authors.lastname: Zierden
authors.affiliation: From the Klinik III für Innere Medizin, Universität zu Köln, Germany (M.V., J.J., E.M.B., L.M., X.C., T.K., M.Z., M.G., H.t.F., S.B., S.R.); Center for Molecular Medicine Cologne (CMMC), Universität zu Köln, Germany (M.V., J.J., E.M.B., L.M., X.C., T.K., M.Z., M.G., H.t.F., S.B., S.R.); Center for R&D, Uppsala University/County Council of Gävleborg, Gävle, Sweden (O.L.); Klinik für Herz- und Thoraxchirurgie, Universität zu Köln, Germany (M.S.); Cologne Cardiovascular Research Center (CCRC), Universität zu Köln, Germany (H.t.F., S.B., S.R.); Klinik für Kardiologie, Charité Universitätsmedizin, Berlin, Germany (F.B.); Institut für Experimentelle Medizin, Universität zu Köln, Germany (A.S.-K.); and Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA (J.J.Z.).
authors.forename: Maximilian
authors.initials: M
authors.lastname: Gerhardt
authors.affiliation: From the Klinik III für Innere Medizin, Universität zu Köln, Germany (M.V., J.J., E.M.B., L.M., X.C., T.K., M.Z., M.G., H.t.F., S.B., S.R.); Center for Molecular Medicine Cologne (CMMC), Universität zu Köln, Germany (M.V., J.J., E.M.B., L.M., X.C., T.K., M.Z., M.G., H.t.F., S.B., S.R.); Center for R&D, Uppsala University/County Council of Gävleborg, Gävle, Sweden (O.L.); Klinik für Herz- und Thoraxchirurgie, Universität zu Köln, Germany (M.S.); Cologne Cardiovascular Research Center (CCRC), Universität zu Köln, Germany (H.t.F., S.B., S.R.); Klinik für Kardiologie, Charité Universitätsmedizin, Berlin, Germany (F.B.); Institut für Experimentelle Medizin, Universität zu Köln, Germany (A.S.-K.); and Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA (J.J.Z.).
authors.forename: Henrik
authors.initials: H
authors.lastname: Ten Freyhaus
authors.affiliation: From the Klinik III für Innere Medizin, Universität zu Köln, Germany (M.V., J.J., E.M.B., L.M., X.C., T.K., M.Z., M.G., H.t.F., S.B., S.R.); Center for Molecular Medicine Cologne (CMMC), Universität zu Köln, Germany (M.V., J.J., E.M.B., L.M., X.C., T.K., M.Z., M.G., H.t.F., S.B., S.R.); Center for R&D, Uppsala University/County Council of Gävleborg, Gävle, Sweden (O.L.); Klinik für Herz- und Thoraxchirurgie, Universität zu Köln, Germany (M.S.); Cologne Cardiovascular Research Center (CCRC), Universität zu Köln, Germany (H.t.F., S.B., S.R.); Klinik für Kardiologie, Charité Universitätsmedizin, Berlin, Germany (F.B.); Institut für Experimentelle Medizin, Universität zu Köln, Germany (A.S.-K.); and Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA (J.J.Z.).
authors.forename: Florian
authors.initials: F
authors.lastname: Blaschke
authors.affiliation: From the Klinik III für Innere Medizin, Universität zu Köln, Germany (M.V., J.J., E.M.B., L.M., X.C., T.K., M.Z., M.G., H.t.F., S.B., S.R.); Center for Molecular Medicine Cologne (CMMC), Universität zu Köln, Germany (M.V., J.J., E.M.B., L.M., X.C., T.K., M.Z., M.G., H.t.F., S.B., S.R.); Center for R&D, Uppsala University/County Council of Gävleborg, Gävle, Sweden (O.L.); Klinik für Herz- und Thoraxchirurgie, Universität zu Köln, Germany (M.S.); Cologne Cardiovascular Research Center (CCRC), Universität zu Köln, Germany (H.t.F., S.B., S.R.); Klinik für Kardiologie, Charité Universitätsmedizin, Berlin, Germany (F.B.); Institut für Experimentelle Medizin, Universität zu Köln, Germany (A.S.-K.); and Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA (J.J.Z.).
authors.forename: Anja
authors.initials: A
authors.lastname: Sterner-Kock
authors.affiliation: From the Klinik III für Innere Medizin, Universität zu Köln, Germany (M.V., J.J., E.M.B., L.M., X.C., T.K., M.Z., M.G., H.t.F., S.B., S.R.); Center for Molecular Medicine Cologne (CMMC), Universität zu Köln, Germany (M.V., J.J., E.M.B., L.M., X.C., T.K., M.Z., M.G., H.t.F., S.B., S.R.); Center for R&D, Uppsala University/County Council of Gävleborg, Gävle, Sweden (O.L.); Klinik für Herz- und Thoraxchirurgie, Universität zu Köln, Germany (M.S.); Cologne Cardiovascular Research Center (CCRC), Universität zu Köln, Germany (H.t.F., S.B., S.R.); Klinik für Kardiologie, Charité Universitätsmedizin, Berlin, Germany (F.B.); Institut für Experimentelle Medizin, Universität zu Köln, Germany (A.S.-K.); and Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA (J.J.Z.).
authors.forename: Stephan
authors.initials: S
authors.lastname: Baldus
authors.affiliation: From the Klinik III für Innere Medizin, Universität zu Köln, Germany (M.V., J.J., E.M.B., L.M., X.C., T.K., M.Z., M.G., H.t.F., S.B., S.R.); Center for Molecular Medicine Cologne (CMMC), Universität zu Köln, Germany (M.V., J.J., E.M.B., L.M., X.C., T.K., M.Z., M.G., H.t.F., S.B., S.R.); Center for R&D, Uppsala University/County Council of Gävleborg, Gävle, Sweden (O.L.); Klinik für Herz- und Thoraxchirurgie, Universität zu Köln, Germany (M.S.); Cologne Cardiovascular Research Center (CCRC), Universität zu Köln, Germany (H.t.F., S.B., S.R.); Klinik für Kardiologie, Charité Universitätsmedizin, Berlin, Germany (F.B.); Institut für Experimentelle Medizin, Universität zu Köln, Germany (A.S.-K.); and Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA (J.J.Z.).
authors.forename: Jean J
authors.initials: JJ
authors.lastname: Zhao
authors.affiliation: From the Klinik III für Innere Medizin, Universität zu Köln, Germany (M.V., J.J., E.M.B., L.M., X.C., T.K., M.Z., M.G., H.t.F., S.B., S.R.); Center for Molecular Medicine Cologne (CMMC), Universität zu Köln, Germany (M.V., J.J., E.M.B., L.M., X.C., T.K., M.Z., M.G., H.t.F., S.B., S.R.); Center for R&D, Uppsala University/County Council of Gävleborg, Gävle, Sweden (O.L.); Klinik für Herz- und Thoraxchirurgie, Universität zu Köln, Germany (M.S.); Cologne Cardiovascular Research Center (CCRC), Universität zu Köln, Germany (H.t.F., S.B., S.R.); Klinik für Kardiologie, Charité Universitätsmedizin, Berlin, Germany (F.B.); Institut für Experimentelle Medizin, Universität zu Köln, Germany (A.S.-K.); and Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA (J.J.Z.). stephan.rosenkranz@uk-koeln.de.
authors.forename: Stephan
authors.initials: S
authors.lastname: Rosenkranz
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000201:enzymology; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000201:enzymology; D058426:Neointima / Q000517:prevention & control; D020033:Protein Isoforms; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction; D066253:Vascular Remodeling / Q000502:physiology*
chemical_list: D020033:Protein Isoforms; D058543:Class Ia Phosphatidylinositol 3-Kinase; D020794:Receptor Protein-Tyrosine Kinases
keywords: neointima; p110; phosphatidylinositol 3′-kinase (PI3K); tyrosine kinase; vascular remodeling; vascular smooth muscle cells