Stability and function of adult vasculature is sustained by Akt/Jagged1 signalling axis in endothelium

Nat Commun. 2016 Mar 14;7:10960. doi: 10.1038/ncomms10960.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiography
  • Animals
  • Biocompatible Materials
  • Blood Vessels / metabolism*
  • Blood-Brain Barrier / metabolism
  • Calcium-Binding Proteins / genetics*
  • Calcium-Binding Proteins / metabolism
  • Collagen
  • Coronary Vessels / metabolism
  • Drug Combinations
  • Echocardiography
  • Endothelial Cells / metabolism*
  • Endothelium / metabolism*
  • Eye / blood supply
  • Fluorescent Antibody Technique
  • Gene Expression Regulation
  • Heart
  • Homeostasis / genetics*
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Immunoblotting
  • Intercellular Signaling Peptides and Proteins / genetics*
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Jagged-1 Protein
  • Laminin
  • Lung / blood supply
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Knockout
  • Muscle, Smooth, Vascular / cytology
  • Myocytes, Smooth Muscle
  • Pericytes
  • Proteoglycans
  • Proto-Oncogene Proteins c-akt / genetics*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Retina
  • Retinal Vessels / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Serrate-Jagged Proteins
  • Signal Transduction / genetics
  • X-Ray Microtomography

Substances

  • Biocompatible Materials
  • Calcium-Binding Proteins
  • Drug Combinations
  • Intercellular Signaling Peptides and Proteins
  • JAG1 protein, human
  • Jag1 protein, mouse
  • Jagged-1 Protein
  • Laminin
  • Membrane Proteins
  • Proteoglycans
  • Serrate-Jagged Proteins
  • matrigel
  • Collagen
  • Akt1 protein, mouse
  • Akt2 protein, mouse
  • Proto-Oncogene Proteins c-akt