Stability and function of adult vasculature is sustained by Akt/Jagged1 signalling axis in endothelium.
Stability and function of adult vasculature is sustained by Akt/Jagged1 signalling axis in endothelium.
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DOI：
10.1038/ncomms10960
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发表时间：
2016-03-14
影响因子：
16.6
通讯作者：
Byzova TV
中科院分区：
文献类型：
--
作者：
Kerr BA;West XZ;Kim YW;Zhao Y;Tischenko M;Cull RM;Phares TW;Peng XD;Bernier-Latmani J;Petrova TV;Adams RH;Hay N;Naga Prasad SV;Byzova TV
在静止的、发育后的脉管系统中运作的信号通路仍然是个谜。在这里，我们表明，与新血管形成，内皮细胞Akt信号在已建立的血管系统是至关重要的不是内皮细胞（EC）的生存，但与周细胞和血管平滑肌细胞（VSMC）调节血管稳定性和功能的持续相互作用。成年全基因Akt 2KO小鼠中可诱导的内皮特异性Akt 1缺失触发进行性VSMC凋亡在心脏中，这会导致动脉和小动脉的损失，尽管毛细血管密度很高，但血管通畅性降低和严重的心脏功能障碍。类似地，内皮Akt缺失诱导视网膜VSMC损失和基底膜恶化，导致血管退化和视网膜萎缩。从机制上讲，Akt/mTOR轴控制内皮Jagged 1的表达，从而Notch信号调节VSMC的维持。Jagged 1肽处理Akt 1 ΔEC; Akt 2KO小鼠和Akt-deficient内皮中Jagged 1再表达恢复VSMC覆盖。因此，持续的内皮Akt 1/2信号传导在维持血管稳定性和体内平衡，从而保护组织和器官功能方面是至关重要的。 Akt通路整合了多种信号，但它是否影响血管功能是有争议的。在这里，作者表明，由于Jagged 1水平降低和Notch信号转导受损，成年小鼠内皮中Akt通路关闭导致血管不稳定，导致心脏和视网膜功能障碍。
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. The Akt pathway integrates multiple signals, but whether it affects vasculature function is debatable. Here the authors show that Akt pathway shutdown in adult mouse endothelium causes destabilization of vasculature leading to cardiac and retinal dysfunction, due to decreased levels of Jagged1 and impaired Notch signaling.