Depletion of ALK5 and Smad4, or inhibition of ALK5 with SB 431542, attenuated TGF-beta1-induced endothelial cell permeability and contraction.
Does inhibition of ALK5 and Smad4 prevent TGF-beta1-induced pulmonary endothelial permeability?
Inhibition of the ALK5/Smad pathway attenuates TGF-beta1-induced pulmonary endothelial barrier dysfunction, highlighting a potential mechanism and therapeutic target for vascular permeability.
The ability of inflammatory cytokine TGF-beta1 to alter endothelial cell phenotype suggests its role in the regulation of vascular endothelial cell permeability. We demonstrate that depletion of TGF-beta1 receptor ALK5 and regulatory protein Smad4, but not ALK1 receptor attenuates TGF-beta1-induced permeability increase and significantly inhibits TGF-beta1-induced EC contraction manifested by actin stress fiber formation and increased MLC and MYPT1 phosphorylation. Consistent with these results, EC treatment with SB 431542, an inhibitor of ALK5 but not ALK1 receptor, significantly attenuates TGF-beta1-induced permeability. Thus, our data demonstrate for the first time direct link between TGF-beta1-mediated activation of ALK5/Smad and EC barrier dysfunction.
Birukova et al. (2005) studied Pulmonary endothelial permeability. Depletion of ALK5 and Smad4 or treatment with SB 431542 vs. Depletion of ALK1 was evaluated on Endothelial cell permeability and contraction. Depletion of ALK5 and Smad4, or inhibition of ALK5 with SB 431542, attenuated TGF-beta1-induced endothelial cell permeability and contraction.