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.
Highlights
The signalling pathways operational in quiescent, post-development vasculature remain enigmatic
It could be anticipated that disruption of Akt signalling in endothelial cell (EC) might result in the loss of endothelial integrity, subsequent thrombosis and sudden death, similar to the phenotype observed by the disruption of the best known Akt activator in endothelium, vascular endothelial growth factor (VEGF)[40]
There was no loss of ECs, and the density of small CD31 þ capillaries even increased in Akt1DEC;Akt2KO hearts (Fig. 1b) resulting in 42-fold higher capillary to arteriole ratios in Akt1DEC;Akt2KO hearts than in WT and Akt2KO hearts (Fig. 1d)
Summary
The signalling pathways operational in quiescent, post-development vasculature remain enigmatic. While some signalling circuits are shared by developmental and postnatal processes[5], recent studies using new inducible and/or tissue-specific KO models revealed that the functions of many key signalling molecules in development are distinct and even opposite from that in postnatal life[6,7] This applies to vasculature, which, once formed during embryonic development, remains relatively quiescent throughout adulthood. We show that EC Akt deletion does not alter EC survival, but instead leads to the gradual loss of VSMCs due to diminished Jagged1/Notch signalling These structural changes in the vasculature result in impaired vessel perfusion and severe tissue dysfunction. Akt signalling is integral in maintaining tissue function by preserving postnatal vessel integrity
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