Transforming growth factor-beta1-induced endothelial barrier dysfunction involves Smad2-dependent p38 activation and subsequent RhoA activation

Journal of Applied Physiology
Qing LuSharon Rounds

Abstract

Lung edema due to increased vascular permeability is a hallmark of acute lung injury and acute respiratory distress syndrome. Both p38 and RhoA signaling events are involved in transforming growth factor (TGF)-beta1-increased endothelial permeability; however, the mechanism by which these pathways cooperate is not clear. In this study, we hypothesized that TGF-beta1-induced changes in endothelial monolayer permeability and in p38 and RhoA activation are dependent on Smad2 signaling. We assessed the role of Smad2 in p38 activation and the role of p38 in RhoA activation by TGF-beta1. We found that TGF-beta1 caused Smad2 phosphorylation between 0.5 and 1 h of exposure in endothelial cells. Knockdown of Smad2 protein prevented TGF-beta1-induced p38 activation and endothelial barrier dysfunction. Furthermore, TGF-beta1-enhanced RhoA activation was dependent on p38 activation. Inhibition of the RhoA-Rho kinase signaling pathway blunted TGF-beta1-induced adherens junction disruption and focal adhesion complex formation. In addition, depletion of heat shock protein 27, a downstream signaling molecule of p38, did not prevent TGF-beta1-induced endothelial barrier dysfunction. Finally, inhibition of de novo protein expression blunted TGF-...Continue Reading

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