Role of Twist1 Phosphorylation in Angiogenesis and Pulmonary Fibrosis.
Idiopathic pulmonary fibrosis is a chronic and progressive lung disease in which microvessel remodeling is deregulated. However, the mechanism by which deregulated angiogenesis contributes to the pathogenesis of pulmonary fibrosis remains unclear. Here we show that a transcription factor, Twist1, controls angiogenesis through the angiopoietin-Tie2 pathway, and that deregulation of this mechanism mediates pathological angiogenesis and collagen deposition in a bleomycin-induced mouse pulmonary fibrosis model. Twist1 knockdown decreases Tie2 expression and attenuates endothelial cell sprouting in vitro. Angiogenesis is also inhibited in fibrin gel implanted on Tie2-specific Twist1 conditional knockout (Twist1fl/fl/Tie2-cre) mouse lung in vivo. Inhibition of Twist1 phosphorylation at the serine 42 (Ser42) residue by treating endothelial cells with a mutant construct (Twist1S42A) decreases Tie2 expression and attenuates angiogenesis compared with full-length Twist1 in vitro and in vivo. Bleomycin challenge up-regulates Twist1 Ser42 phosphorylation and Tie2 expression, increases blood vessel density, and induces collagen deposition in the mouse lung, whereas these effects are attenuated in Twist1fl/fl/Tie2-cre mice or in mice treated with Twist1S42A mutant construct. These results indicate that Twist1 Ser42 phosphorylation contributes to the pathogenesis of bleomycin-induced pulmonary fibrosis through angiopoietin-Tie2 signaling.
Vascular Biology Program, Department of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.
Tadanori
T
Mammoto
Vascular Biology Program, Department of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.
Amanda
A
Jiang
Vascular Biology Program, Department of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.
Elisabeth
E
Jiang
Vascular Biology Program, Department of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.
Akiko
A
Mammoto
D000818:Animals; D001761:Bleomycin; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D005337:Fibrin / Q000494:pharmacology; D005782:Gels; D055785:Gene Knockdown Techniques; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051379:Mice; D018919:Neovascularization, Physiologic / Q000187:drug effects; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000378:metabolism* / Q000473:pathology; D042787:Receptor, TIE-2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051879:Twist-Related Protein 1 / Q000378:metabolism*
D005782:Gels; D009687:Nuclear Proteins; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1; D001761:Bleomycin; C067250:Twist1 protein, mouse; D010768:Phosphoserine; D005337:Fibrin; D003094:Collagen; D042787:Receptor, TIE-2
Tie2; Twist1; angiogenesis; phosphorylation; pulmonary fibrosis