Endothelial Twist1-PDGFB signaling mediates hypoxia-induced proliferation and migration of αSMA-positive cells. Sci Rep 2020 May 05;10(1):7563
Date
05/07/2020Pubmed ID
32371931Pubmed Central ID
PMC7200682DOI
10.1038/s41598-020-64298-5Scopus ID
2-s2.0-85084328882 (requires institutional sign-in at Scopus site) 16 CitationsAbstract
Remodeling of distal pulmonary arterioles (PAs) associated with marked accumulation of pulmonary artery smooth muscle cells (PASMCs) represents one of the major pathologic features of pulmonary hypertension (PH). We have reported that the transcription factor Twist1 mediates hypoxia-induced PH. However, the mechanism by which endothelial Twist1 stimulates SMC accumulation to distal PAs in PH remains unclear. Here, we have demonstrated that Twist1 overexpression increases the expression of platelet-derived growth factor (PDGFB) in human pulmonary arterial endothelial (HPAE) cells. Hypoxia upregulates the levels of Twist1 and PDGFB in HPAE cells. When we implant hydrogel supplemented with endothelial cells (ECs) on the mouse lung, these ECs form vascular lumen structures and hypoxia upregulates PDGFB expression and stimulates accumulation of αSMA-positive cells in the gel, while knockdown of endothelial Twist1 suppresses the effects. The levels of Twist1 and PDGFB are higher in PAE cells isolated from idiopathic pulmonary arterial hypertension (IPAH) patients compared to those from healthy controls. IPAH patient-derived PAE cells stimulate accumulation of αSMA-positive cells in the implanted gel, while Twist1 knockdown in PAE cells inhibits the effects. Endothelial Twist1-PDGFB signaling plays a key role in αSMA-positive cell proliferation and migration in PH.
Author List
Mammoto A, Hendee K, Muyleart M, Mammoto TAuthors
Kathryn Hendee in the CTSI department at Medical College of Wisconsin - CTSIAkiko 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
ActinsAnimals
Cell Movement
Cell Proliferation
Endothelial Cells
Humans
Hypoxia
Mice
Muscle, Smooth, Vascular
Nuclear Proteins
Proto-Oncogene Proteins c-sis
Signal Transduction
Twist-Related Protein 1