Faculty Collaboration Database

Role of Twist1 Phosphorylation in Angiogenesis and Pulmonary Fibrosis. Am J Respir Cell Mol Biol 2016 Nov;55(5):633-644

Date

11/01/2016

Pubmed ID

27281171

DOI

10.1165/rcmb.2016-0012OC

Scopus ID

2-s2.0-84994417658 (requires institutional sign-in at Scopus site)   41 Citations

Abstract

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 (Twist1^fl/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 Twist1^fl/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.

Author List

Mammoto T, Jiang A, Jiang E, Mammoto A

Authors

Akiko Mammoto MD, PhD Associate Professor in the Pediatrics department at Medical College of Wisconsin
Tadanori Mammoto MD, PhD Associate Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Bleomycin
Collagen
Disease Models, Animal
Fibrin
Gels
Gene Knockdown Techniques
Human Umbilical Vein Endothelial Cells
Humans
Mice
Neovascularization, Physiologic
Nuclear Proteins
Phosphorylation
Phosphoserine
Pulmonary Fibrosis
Receptor, TIE-2
Signal Transduction
Twist-Related Protein 1