内皮细胞中的Akt1通过磷酸化多种血管生成底物来介导血管生成。 - Suppr | 超能文献

Abstract

The PI3K/Akt pathway is necessary for several key endothelial cell (EC) functions, including cell growth, migration, survival, and vascular tone. However, existing literature supports the idea that Akt can be either pro- or antiangiogenic, possibly due to compensation by multiple isoforms in the EC when a single isoform is deleted. Thus, biochemical, genetic, and proteomic studies were conducted to examine isoform-substrate specificity for Akt1 vs. Akt2. In vitro, Akt1 preferentially phosphorylates endothelial nitric oxide synthase (eNOS) and promotes NO release, whereas nonphysiological overexpression of Akt2 can bypass the loss of Akt1. Conditional deletion of Akt1 in the EC, in the absence or presence of Akt2, retards retinal angiogenesis, implying that Akt1 exerts a nonredundant function during physiological angiogenesis. Finally, proteomic analysis of Akt substrates isolated from Akt1- or Akt2-deficient ECs documents that phosphorylation of multiple Akt substrates regulating angiogenic signaling is reduced in Akt1-deficient, but not Akt2-deficient, ECs, including eNOS and Forkhead box proteins. Therefore, Akt1 promotes angiogenesis largely due to phosphorylation and regulation of important downstream effectors that promote aspects of angiogenic signaling.

摘要

PI3K/Akt信号通路对于几种关键的内皮细胞（EC）功能是必需的，包括细胞生长、迁移、存活和血管张力。然而，现有文献支持Akt可能具有促血管生成或抗血管生成作用的观点，这可能是由于在EC中当单个亚型被缺失时多种亚型之间的补偿作用。因此，开展了生化、遗传和蛋白质组学研究来检测Akt1与Akt2的亚型-底物特异性。在体外，Akt1优先磷酸化内皮型一氧化氮合酶（eNOS）并促进NO释放，而Akt2的非生理性过表达可绕过Akt1的缺失。在存在或不存在Akt2的情况下，EC中Akt1的条件性缺失会延缓视网膜血管生成，这意味着Akt1在生理性血管生成过程中发挥着非冗余功能。最后，从Akt1或Akt2缺陷的EC中分离出的Akt底物的蛋白质组学分析表明，在Akt1缺陷而非Akt2缺陷的EC中，调节血管生成信号的多种Akt底物的磷酸化减少，包括eNOS和叉头框蛋白。因此，Akt1主要通过磷酸化和调节促进血管生成信号各方面的重要下游效应器来促进血管生成。