TAK1 Signaling Downstream of PAR-1 in Endothelial Cells Restores Lung Vascular Barrier Integrity

The proinflammatory mediator thrombin increases vascular permeability by disassembling vascular endothelial adherens junctions (AJs). However, the intrinsic signaling mechanisms that mediate the reassembly of endothelial AJs are poorly understood. Here we show that transforming growth factor-β-activated kinase (TAK1) activation downstream of protease-activated receptor-1 (PAR-1) signals the reassembly of endothelial AJs. PAR-1 agonist, thrombin induced a time-dependent phosphorylation of TAK1 in lung endothelial cells (ECs). Silencing of stromal interaction molecule 1 (STIM1) suppressed thrombin-induced TAK1 phosphorylation in ECs, indicating that store-operated calcium entry (SOCE) is essential for PAR-1-mediated TAK1 activation. Inhibition of TAK1 augmented thrombin-induced permeability increase both in vitro and in intact lung microvessels. Consistent with these findings, inhibition of TAK1 impaired reassembly VE-cadherin at AJs after thrombin treatment. We also observed that thrombin-induced SOCE was ...