ALK5 and Smad4 are involved in TGF-beta1-induced pulmonary endothelial 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
Anna A
AA
Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA.
Adyshev
Djanibek
D
Gorshkov
Boris
B
Birukov
Konstantin G
KG
Verin
Alexander D
AD
D000199:Actins / Q000378:metabolism; D030201:Activin Receptors, Type I / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D015153:Blotting, Western; D002417:Cattle; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology*; D004149:Dioxoles / Q000494:pharmacology; D017097:Electric Impedance; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D008168:Lung / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D043263:Myosin-Light-Chain Phosphatase / Q000378:metabolism; D009218:Myosins / Q000737:chemistry; D010539:Permeability; D010641:Phenotype; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051901:Smad4 Protein; D013997:Time Factors; D015534:Trans-Activators / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1; D014404:Tubulin / Q000378:metabolism
C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D000199:Actins; D001549:Benzamides; D004268:DNA-Binding Proteins; D004149:Dioxoles; D034741:RNA, Small Interfering; D018125:Receptors, Transforming Growth Factor beta; D051901:Smad4 Protein; C508960:TGFB1 protein, human; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D014404:Tubulin; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human; D043263:Myosin-Light-Chain Phosphatase; C490372:PPP1R12A protein, human; D009218:Myosins