title: Stability and function of adult vasculature is sustained by Akt/Jagged1 signalling axis in endothelium.
abstract: The signalling pathways operational in quiescent, post-development vasculature remain enigmatic. Here we show that unlike neovascularization, endothelial Akt signalling in established vasculature is crucial not for endothelial cell (EC) survival, but for sustained interactions with pericytes and vascular smooth muscle cells (VSMCs) regulating vascular stability and function. Inducible endothelial-specific Akt1 deletion in adult global Akt2KO mice triggers progressive VSMC apoptosis. In hearts, this causes a loss of arteries and arterioles and, despite a high capillary density, diminished vascular patency and severe cardiac dysfunction. Similarly, endothelial Akt deletion induces retinal VSMC loss and basement membrane deterioration resulting in vascular regression and retinal atrophy. Mechanistically, the Akt/mTOR axis controls endothelial Jagged1 expression and, thereby, Notch signalling regulating VSMC maintenance. Jagged1 peptide treatment of Akt1ΔEC;Akt2KO mice and Jagged1 re-expression in Akt-deficient endothelium restores VSMC coverage. Thus, sustained endothelial Akt1/2 signalling is critical in maintaining vascular stability and homeostasis, thereby preserving tissue and organ function.
authors.affiliation: Department of Molecular Cardiology, Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Bethany A
authors.identifier: http://orcid.org/0000-0002-2995-7549
authors.initials: BA
authors.lastname: Kerr
authors.affiliation: Department of Molecular Cardiology, Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Xiaoxia Z
authors.initials: XZ
authors.lastname: West
authors.affiliation: Department of Molecular Cardiology, Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Young-Woong
authors.initials: YW
authors.lastname: Kim
authors.affiliation: Department of Molecular Cardiology, Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Yongzhong
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Molecular Cardiology, Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Miroslava
authors.initials: M
authors.lastname: Tischenko
authors.affiliation: Department of Molecular Cardiology, Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Cull
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Phares
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Illinois College of Medicine at Chicago, Chicago, Illinois 60607, USA.
authors.forename: Xiao-Ding
authors.initials: XD
authors.lastname: Peng
authors.affiliation: Department of Fundamental Oncology, Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne, Lausanne CH-1066, Switzerland.
authors.forename: Jeremiah
authors.initials: J
authors.lastname: Bernier-Latmani
authors.affiliation: Department of Fundamental Oncology, Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne, Lausanne CH-1066, Switzerland.
authors.forename: Tatiana V
authors.initials: TV
authors.lastname: Petrova
authors.affiliation: Department of Tissue Morphogenesis, Max Planck Institute for Molecular Biomedicine, Münster 48149, Germany.|Faculty of Medicine, University of Münster, Münster 48149, Germany.
authors.forename: Ralf H
authors.identifier: http://orcid.org/0000-0003-3031-7677
authors.initials: RH
authors.lastname: Adams
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Illinois College of Medicine at Chicago, Chicago, Illinois 60607, USA.
authors.forename: Nissim
authors.initials: N
authors.lastname: Hay
authors.affiliation: Department of Molecular Cardiology, Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Sathyamangla V
authors.initials: SV
authors.lastname: Naga Prasad
authors.affiliation: Department of Molecular Cardiology, Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Tatiana V
authors.initials: TV
authors.lastname: Byzova
mesh_terms: D000792:Angiography; D000818:Animals; D001672:Biocompatible Materials; D001808:Blood Vessels / Q000378:metabolism*; D001812:Blood-Brain Barrier / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D003094:Collagen; D003331:Coronary Vessels / Q000378:metabolism; D004338:Drug Combinations; D004452:Echocardiography; D042783:Endothelial Cells / Q000378:metabolism*; D004727:Endothelium / Q000378:metabolism*; D005123:Eye / Q000098:blood supply; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation; D006321:Heart; D006706:Homeostasis / Q000235:genetics*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D015151:Immunoblotting; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D000072100:Jagged-1 Protein; D007797:Laminin; D008168:Lung / Q000098:blood supply; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle; D020286:Pericytes; D011509:Proteoglycans; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics* / Q000378:metabolism; D012160:Retina; D012171:Retinal Vessels / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000235:genetics; D055114:X-Ray Microtomography
chemical_list: D001672:Biocompatible Materials; D002135:Calcium-Binding Proteins; D004338:Drug Combinations; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D007797:Laminin; D008565:Membrane Proteins; D011509:Proteoglycans; D000072099:Serrate-Jagged Proteins; C059485:matrigel; D003094:Collagen; C514862:Akt1 protein, mouse; C494922:Akt2 protein, mouse; D051057:Proto-Oncogene Proteins c-akt