Kerr Bethany A, West Xiaoxia Z, Kim Young-Woong, Zhao Yongzhong, Tischenko Miroslava, Cull Rebecca M, Phares Timothy W, Peng Xiao-Ding, Bernier-Latmani Jeremiah, Petrova Tatiana V, Adams Ralf H, Hay Nissim, Naga Prasad Sathyamangla V, Byzova Tatiana V
Department of Molecular Cardiology, Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
Nat Commun. 2016 Mar 14;7:10960. doi: 10.1038/ncomms10960.
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.
在静止的、发育后的脉管系统中起作用的信号通路仍然是个谜。在这里，我们表明，与新生血管形成不同，成熟脉管系统中的内皮Akt信号传导对于内皮细胞（EC）存活并非至关重要，而是对于与周细胞和血管平滑肌细胞（VSMC）的持续相互作用至关重要，这些相互作用调节血管稳定性和功能。成年全局Akt2基因敲除小鼠中可诱导的内皮特异性Akt1缺失引发渐进性VSMC凋亡。在心脏中，这会导致动脉和小动脉丧失，尽管毛细血管密度很高，但血管通畅性降低和严重的心功能障碍。同样，内皮Akt缺失会诱导视网膜VSMC丧失和基底膜退化，导致血管消退和视网膜萎缩。从机制上讲，Akt/mTOR轴控制内皮Jagged1表达，从而控制调节VSMC维持的Notch信号传导。用Jagged1肽处理Akt1ΔEC;Akt2基因敲除小鼠并在Akt缺陷的内皮中重新表达Jagged1可恢复VSMC覆盖。因此，持续的内皮Akt1/2信号传导对于维持血管稳定性和体内平衡至关重要，从而保护组织和器官功能。
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