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

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posted on 08.08.2016 by BA Kerr, XZ West, YW Kim, Y Zhao, M Tischenko, RM Cull, TW Phares, XD Peng, J Bernier-Latmani, TV Petrova, RH Adams, N Hay, SV Naga Prasad, TV Byzova
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.

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This study was supported by research funding from NIH grant HL071625 to T.V.B. B.A.K was supported by a Ruth L. Kirschstein NRSA award (CA142133) from the NIH/NCI. Y.W.K. was supported by an AHA Postdoctoral Fellowship (POST14570001).

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This is a copy of an article published in Nature Communications. © 2016 Nature Publishing Group Publications. © The Author(s). http://www.nature.com/naturecommunications

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Nature Publishing Group

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en_US

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14/03/2016

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