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

Bethany A. Kerr, Xiaoxia Z. West, Young-Woong Kim, Yongzhong Zhao, Miroslava Tischenko, Rebecca M. Cull, Timothy W. Phares, Xiao-Ding Peng, Jeremiah Bernier-Latmani, Tatiana V. Petrova, Ralf H. Adams, Nissim Hay, Sathyamangla V. Naga Prasad and Tatiana V. Byzova ()
Additional contact information
Bethany A. Kerr: Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Lerner Research Institute, Cleveland Clinic
Xiaoxia Z. West: Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Lerner Research Institute, Cleveland Clinic
Young-Woong Kim: Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Lerner Research Institute, Cleveland Clinic
Yongzhong Zhao: Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Lerner Research Institute, Cleveland Clinic
Miroslava Tischenko: Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Lerner Research Institute, Cleveland Clinic
Rebecca M. Cull: Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Lerner Research Institute, Cleveland Clinic
Timothy W. Phares: Lerner Research Institute, Cleveland Clinic
Xiao-Ding Peng: University of Illinois College of Medicine at Chicago
Jeremiah Bernier-Latmani: Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne
Tatiana V. Petrova: Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne
Ralf H. Adams: Max Planck Institute for Molecular Biomedicine
Nissim Hay: University of Illinois College of Medicine at Chicago
Sathyamangla V. Naga Prasad: Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Lerner Research Institute, Cleveland Clinic
Tatiana V. Byzova: Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Lerner Research Institute, Cleveland Clinic

Nature Communications, 2016, vol. 7, issue 1, 1-18

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms10960

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