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

被引：68

作者：

Kerr, Bethany A. ^{[1
]}

West, Xiaoxia Z. ^{[1
]}

Kim, Young-Woong ^{[1
]}

Zhao, Yongzhong ^{[1
]}

Tischenko, Miroslava ^{[1
]}

Cull, Rebecca M. ^{[1
]}

Phares, Timothy W. ^{[2
]}

Peng, Xiao-Ding ^{[3
]}

Bernier-Latmani, Jeremiah ^{[4
,5
]}

Petrova, Tatiana V. ^{[4
,5
]}

Adams, Ralf H. ^{[6
,7
]}

Hay, Nissim ^{[3
]}

Prasad, Sathyamangla V. Naga ^{[1
]}

Byzova, Tatiana V. ^{[1
]}

机构：

[1] Cleveland Clin, Dept Mol Cardiol, Joseph J Jacobs Ctr Thrombosis & Vasc Biol, Lerner Res Inst, Cleveland, OH 44195 USA

[2] Cleveland Clin, Dept Neurosci, Lerner Res Inst, Cleveland, OH 44195 USA

[3] Univ Illinois, Coll Med Chicago, Dept Biochem & Mol Genet, Chicago, IL 60607 USA

[4] CHU Vaudois, Dept Fundamental Oncol, CH-1066 Lausanne, Switzerland

[5] Univ Lausanne, CH-1066 Lausanne, Switzerland

[6] Max Planck Inst Mol Biomed, Dept Tissue Morphogenesis, D-48149 Munster, Germany

[7] Univ Munster, Fac Med, D-48149 Munster, Germany

来源：

NATURE COMMUNICATIONS | 2016年 / 7卷

关键词：

INHIBITS TUMOR-GROWTH; PATHOLOGICAL ANGIOGENESIS; CARDIOVASCULAR-DISEASE; P110-ALPHA ISOFORM; CLINICAL-TRIAL; IN-VIVO; AKT; NOTCH; CELL; JAGGED1;

D O I：

10.1038/ncomms10960

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 Akt1 Delta EC; 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.

引用

页数：18

共 70 条

[1] Akt1/protein kinase Bα is critical for ischemic and VEGF-mediated angiogenesis [J].