Akt1 promotes stimuli-induced endothelial-barrier protection through FoxO-mediated tight-junction protein turnover

Fei Gao, Sandeep Artham, Harika Sabbineni, Ahmad Al-Azayzih, Xiao Ding Peng, Nissim Hay, Ralf H. Adams, Tatiana V. Byzova, Payaningal R. Somanath

Research output: Contribution to journalArticlepeer-review

30 Citations (Scopus)

Abstract

Vascular permeability regulated by the vascular endothelial growth factor (VEGF) through endothelial-barrier junctions is essential for inflammation. Mechanisms regulating vascular permeability remain elusive. Although ‘Akt’ and ‘Src’ have been implicated in the endothelial-barrier regulation, it is puzzling how both agents that protect and disrupt the endothelial-barrier activate these kinases to reciprocally regulate vascular permeability. To delineate the role of Akt1 in endothelial-barrier regulation, we created endothelial-specific, tamoxifen-inducible Akt1 knockout mice and stable ShRNA-mediated Akt1 knockdown in human microvascular endothelial cells. Akt1 loss leads to decreased basal and angiopoietin1-induced endothelial-barrier resistance, and enhanced VEGF-induced endothelial-barrier breakdown. Endothelial Akt1 deficiency resulted in enhanced VEGF-induced vascular leakage in mice ears, which was rescued upon re-expression with Adeno-myrAkt1. Furthermore, co-treatment with angiopoietin1 reversed VEGF-induced vascular leakage in an Akt1-dependent manner. Mechanistically, our study revealed that while VEGF-induced short-term vascular permeability is independent of Akt1, its recovery is reliant on Akt1 and FoxO-mediated claudin expression. Pharmacological inhibition of FoxO transcription factors rescued the defective endothelial barrier due to Akt1 deficiency. Here we provide novel insights on the endothelial-barrier protective role of VEGF in the long term and the importance of Akt1-FoxO signaling on tight-junction stabilization and prevention of vascular leakage through claudin expression.

Original languageEnglish
Pages (from-to)3917-3933
Number of pages17
JournalCellular and Molecular Life Sciences
Volume73
Issue number20
DOIs
Publication statusPublished - Oct 1 2016
Externally publishedYes

Keywords

  • Akt
  • Angiopoietin-1
  • Claudin
  • VE-cadherin
  • VEGF
  • Vascular permeability

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Cellular and Molecular Neuroscience
  • Cell Biology

Fingerprint

Dive into the research topics of 'Akt1 promotes stimuli-induced endothelial-barrier protection through FoxO-mediated tight-junction protein turnover'. Together they form a unique fingerprint.

Cite this