Akt1 promotes stimuli-induced endothelial-barrier protection through FoxO-mediated tight-junction protein turnover.
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.
Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia and Charlie Norwood VA Medical Center, Augusta, GA, USA.|Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Fei
F
Gao
Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia and Charlie Norwood VA Medical Center, Augusta, GA, USA.
Sandeep
S
Artham
Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia and Charlie Norwood VA Medical Center, Augusta, GA, USA.
Harika
H
Sabbineni
Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia and Charlie Norwood VA Medical Center, Augusta, GA, USA.|College of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan.
Ahmad
A
Al-Azayzih
Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
Xiao-Ding
XD
Peng
Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
Nissim
N
Hay
Max Plank Institute of Molecular Biomedicine, Röntgenstraße 20, Münster, Germany.
Ralf H
RH
Adams
Department of Molecular Cardiology, Joseph J. Jacob's Center for Thrombosis and Vascular Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
Tatiana V
TV
Byzova
Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia and Charlie Norwood VA Medical Center, Augusta, GA, USA. sshenoy@augusta.edu.|Department of Medicine and Vascular Biology Center, Augusta University, HM1200, Augusta, GA, 30912, USA. sshenoy@augusta.edu.
Payaningal R
PR
Somanath
D022005:Adherens Junctions / Q000187:drug effects / Q000378:metabolism; D042683:Angiopoietin-1 / Q000494:pharmacology; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D062507:Claudin-5 / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D000071316:Forkhead Box Protein O3 / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D008822:Mice, Transgenic; D055806:Microvessels / Q000166:cytology; D051057:Proto-Oncogene Proteins c-akt / Q000172:deficiency / Q000378:metabolism*; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism*; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
D042683:Angiopoietin-1; D062507:Claudin-5; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D042461:Vascular Endothelial Growth Factor A; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3
Akt; Angiopoietin-1; Claudin; VE-cadherin; VEGF; Vascular permeability