Regulation of Ang2 release by PTEN/PI3-kinase/Akt in lung microvascular endothelial cells.
Angiopoietin-2 (Ang2) is a Tie-2 ligand that destabilizes vascular structures, allowing for neovascularization or vessel regression depending on local vascular endothelial cell growth factor (VEGF) concentrations. Although various stimuli have been shown to affect Ang2 expression, information on the underlying mechanisms involved in Ang2 production in endothelial cells (EC) is just beginning to emerge. In the present study, we have used adenovirus-mediated gene transfer and pharmacological inhibitors to examine the role of the PTEN/PI3-K/Akt pathway on Ang2 release. Inhibition of PI3-kinase with wortmannin led to a stimulation of basal Ang2 release in EC, while overexpression of an active form of Akt reduced Ang2. In addition, adenovirus-mediated gene transfer of the phosphatase PTEN stimulated Ang2 release. Incubation of the cells with Ang1, an agent that activates the PI3-K/Akt pathway in EC, reduced Ang2 release. This effect of Ang1 could be prevented by wortmannin and LY-294002 pretreatment. Similarly, in VEGF-treated EC the increase in Ang2 production observed was greater in the presence of a PI3-K inhibitor. Our observations that PTEN acts as a positive modulator of Ang2 release, while activation of the PI3-K/Akt pathway downregulates Ang2, reveal an additional mechanism through which the PTEN/PI3-K/Akt pathway could affect the angiogenic process.
Tsigkos
Stelios
S
"G.P. Livanos and M. Simou" Laboratories, Evangelismos Hospital, Critical Care Department, University of Athens School of Medicine, Athens, Greece.
Zhou
Zongmin
Z
Kotanidou
Anastasia
A
Fulton
David
D
Zakynthinos
Spyros
S
Roussos
Charis
C
Papapetropoulos
Andreas
A
D000730:Androstadienes / Q000494:pharmacology; D042683:Angiopoietin-1 / Q000494:pharmacology; D042702:Angiopoietin-2 / Q000378:metabolism*; D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D008168:Lung / Q000166:cytology; D009025:Morpholines / Q000494:pharmacology; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D000077191:Wortmannin
D000730:Androstadienes; D042683:Angiopoietin-1; D042702:Angiopoietin-2; D002867:Chromones; D004791:Enzyme Inhibitors; D005419:Flavonoids; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D042461:Vascular Endothelial Growth Factor A; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D000077191:Wortmannin