Tumor necrosis factor-related apoptosis-inducing ligand promotes microvascular endothelial cell hyperpermeability through phosphatidylinositol 3-kinase pathway

Hayden W. Stagg, Kanika A. Bowen, Devendra A. Sawant, Miguel Rodriguez, Binu Tharakan, Ed W. Childs

Research output: Contribution to journalArticle

9 Scopus citations


Background: Microvascular hyperpermeability that occurs in hemorrhagic shock and burn trauma is regulated by the apoptotic signaling pathway. We hypothesized that tumor necrosis factor-α (TNF-α)-related apoptosis-inducing ligand (TRAIL) would promote hyperpermeability directly or by interacting with other signaling pathways. Methods: Rat lung microvascular endothelial cells (RLMECs) grown on Transwell membranes (Corning Life Sciences, Lowell, MA) were treated with recombinant human TRAIL (10, 50, and 100 ng/mL) for 6 hours or TRAIL (100 ng/mL) + LY294002 (a PI3K inhibitor; 20 μmol/L), Z-DEVD-FMK (a caspase-3 inhibitor; 10 μmol/L), or the inhibitors alone. Fluorescein isothiocyanate (FITC)-albumin flux was an indicator of permeability. Caspase-3 activity was measured fluorometrically. Adherens junction integrity was studied using β-catenin immunofluorescence. Results: TRAIL + LY294002, but not TRAIL alone, induced monolayer hyperpermeability (P < .05), and caspase-3 activity (P <.05), and disrupted the adherens junctions. Z-DEVD-FMK attenuated hyperpermeability and protected the adherens junctions. Conclusions: TRAIL-induced microvascular hyperpermeability is phosphatidylinositol 3-kinase (PI3K)-dependent and may be mediated by caspase-3 cleavage of the endothelial adherens junctional complex.

Original languageEnglish (US)
Pages (from-to)419-425
Number of pages7
JournalAmerican Journal of Surgery
Issue number4
StatePublished - Apr 1 2013
Externally publishedYes



  • Apoptotic signaling
  • PI3K
  • Vascular permeability

ASJC Scopus subject areas

  • Surgery

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