发病机制
肺
PDGFB公司
肺动脉高压
肺动脉
缺氧(环境)
医学
下调和上调
基因敲除
病理
癌症研究
免疫学
化学
内科学
生物
生长因子
血小板源性生长因子受体
细胞培养
有机化学
氧气
受体
基因
生物化学
遗传学
作者
Akiko Mammoto,Tadanori Mammoto
标识
DOI:10.1096/fasebj.2019.33.1_supplement.550.14
摘要
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). The levels of a transcription factor, Twist1 are upregulated in the lungs of patients with pulmonary arterial hypertension (PAH). However, the mechanism by which endothelial Twist1 stimulates SMC accumulation to distal PAs in PH remains unclear. Here we have 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 SMC migration and growth. Knockdown of Twist1 in ECs attenuates hypoxia‐induced accumulation of alpha‐smooth muscle actin (SMA)‐positive cells to the PAs in mice. To further study the mechanism by which endothelial Twist1 controls vascular remodeling and SMC accumulation in the lung, we implant fibrin gel supplemented with fluorescently labeled HPAECs on the mouse lung. Supplemented HPAECs form vascular structures and hypoxia treatment stimulates accumulation of alpha‐SMA–positive cells to blood vessels and upregulates expression of PDGFB in the gel. Twist1 overexpression in supplemented HPAECs or hypoxia treatment also induces endothelial‐to‐mesenchymal transition (EndMT) in the implanted gel, which also partly contributes to the pathogenesis of PH. Endothelial Twist1 plays a key role in SMC accumulation to PAs through PDGFB signaling and the mouse lung gel implantation system would be a good model system to study the pathogenesis of PH and other lung diseases. Support or Funding Information AHA18TPA34170129, MCW Research Affair Committee New Investigator Award This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
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