Twist1 in Hypoxia-induced Pulmonary Hypertension through Transforming Growth Factor-β-Smad Signaling.

Abstract

Pulmonary hypertension (PH) is a devastating pulmonary vascular disease characterized by aberrant muscularization of the normally nonmuscularized distal pulmonary arterioles. The expression of the transcription factor, Twist1, increases in the lungs of patients with pulmonary arterial hypertension. However, the mechanisms by which Twist1 controls the pathogenesis of PH remain unclear. It is becoming clear that endothelial-to-mesenchymal transition (EndMT) contributes to various vascular pathologies, including PH; Twist1 is known to mediate EndMT. In this report, we demonstrate that Twist1 overexpression increases transforming growth factor (TGF) β receptor2 (TGF-βR2) expression and Smad2 phosphorylation, and induces EndMT in cultured human pulmonary arterial endothelial (HPAE) cells, whereas a mutant construct of Twist1 at the serine 42 residue (Twist1S42A) fails to induce EndMT. We also implanted fibrin gel supplemented with HPAE cells on the mouse lung, and found that these HPAE cells form vascular structures and that Twist1-overexpressing HPAE cells undergo EndMT in the gel, whereas Twist1S42A-overexpressing cells do not. Furthermore, hypoxia-induced EndMT is inhibited in endothelial cells overexpressing Twist1S42A mutant construct in vitro. Hypoxia-induced accumulation of α-smooth muscle actin-positive cells in the pulmonary arterioles is attenuated in Tie2-specific Twist1 conditional knockout mice in vivo. These findings suggest that Twist1 serine 42 phosphorylation plays a key role in EndMT through TGF-β signaling and that modulation of Twist1 phosphorylation could be an effective strategy for managing PH.

• Authors: Tadanori Mammoto, Megan Muyleart, G Ganesh Konduri, Akiko Mammoto
• Journal: American journal of respiratory cell and molecular biology (Am J Respir Cell Mol Biol) Vol. 58 Issue 2 Pg. 194-207 (02 2018) ISSN: 1535-4989 [Electronic] United States
• PMID: 28915063 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Nuclear Proteins
• Receptors, Transforming Growth Factor beta
• Smad2 Protein
• Smad2 protein, mouse
• Transforming Growth Factor beta
• Twist-Related Protein 1
• Twist1 protein, mouse

Topics

• Animals
• Cell Hypoxia (physiology)
• Cells, Cultured
• Endothelial Cells (metabolism)
• Humans
• Hypertension, Pulmonary (pathology)
• Lung (pathology)
• Mice
• Mice, Knockout
• Nuclear Proteins (genetics, metabolism)
• Pulmonary Artery (pathology)
• Receptors, Transforming Growth Factor beta (metabolism)
• Smad2 Protein (metabolism)
• Transforming Growth Factor beta (metabolism)
• Twist-Related Protein 1 (genetics, metabolism)