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Twist1 in Hypoxia‐induced Pulmonary Vascular Remodeling
Author(s) -
Mammoto Akiko,
Hendee Kathryn,
Mammoto Tadanori
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.03695
Subject(s) - pdgfb , gene knockdown , hypoxia (environmental) , pulmonary artery , medicine , pulmonary hypertension , cancer research , pathology , microbiology and biotechnology , chemistry , biology , growth factor , platelet derived growth factor receptor , apoptosis , biochemistry , receptor , organic chemistry , oxygen
Remodeling of distal pulmonary arterioles (PAs) associated with accumulation of pulmonary artery smooth muscle cells (PASMCs) represents one of the major pathologic features of pulmonary hypertension (PH). We have reported that a transcription factor, Twist1 in endothelial cells (ECs) contributes to hypoxia‐induced PH. However, the mechanism by which endothelial Twist1 controls SMC accumulation to PAs remains unclear. Here we found that Twist1 overexpression increases the expression of platelet‐derived growth factor (PDGFB) in cultured human pulmonary arterial endothelial cells (HPAECs). Conditioned media collected from Twist1 overexpressing HPAECs induce PASMC migration and proliferation. Hypoxia upregulates the levels of Twist1 and PDGFB in HPAECs. When we implant fibrin gel supplemented with ECs on the mouse lung, these ECs form vascular lumen structures and hypoxia stimulates accumulation of alpha smooth muscle actin (αSMA)–positive cells to blood vessels and upregulates PDGFB expression in the gel, while Twist1 knockdown in ECs suppresses the effects. The levels of Twist1 and PDGFB are higher in PAECs isolated from idiopathic pulmonary arterial hypertension (IPAH) patients compared to those from healthy controls. IPAH patient‐derived PAECs stimulate accumulation of αSMA–positive cells to blood vessels in the implanted gel, while knockdown of Twist1 inhibits the effects. These findings suggest that endothelial Twist1‐PDGFB signaling plays a key role in SMC accumulation to PAs in PH. Modulation of Twist1‐PDGFB signaling could be an effective strategy for PH. Support or Funding Information NIHR01HL139638, AHA18TPA34170129