| Autor: |
Dougherty EJ; Clinical Center/Critical Care Medicine Department, National Institutes of Health, Bethesda, Maryland, United States., Chen LY; Clinical Center/Critical Care Medicine Department, National Institutes of Health, Bethesda, Maryland, United States., Awad KS; Clinical Center/Critical Care Medicine Department, National Institutes of Health, Bethesda, Maryland, United States., Ferreyra GA; Clinical Center/Critical Care Medicine Department, National Institutes of Health, Bethesda, Maryland, United States., Demirkale CY; Clinical Center/Critical Care Medicine Department, National Institutes of Health, Bethesda, Maryland, United States., Keshavarz A; Clinical Center/Critical Care Medicine Department, National Institutes of Health, Bethesda, Maryland, United States., Gairhe S; Clinical Center/Critical Care Medicine Department, National Institutes of Health, Bethesda, Maryland, United States., Johnston KA; Clinical Center/Critical Care Medicine Department, National Institutes of Health, Bethesda, Maryland, United States., Hicks ME; Clinical Center/Critical Care Medicine Department, National Institutes of Health, Bethesda, Maryland, United States., Sandler AB; Clinical Center/Critical Care Medicine Department, National Institutes of Health, Bethesda, Maryland, United States., Curran CS; Clinical Center/Critical Care Medicine Department, National Institutes of Health, Bethesda, Maryland, United States., Krack JM; Clinical Center/Critical Care Medicine Department, National Institutes of Health, Bethesda, Maryland, United States., Ding Y; Clinical Center/Critical Care Medicine Department, National Institutes of Health, Bethesda, Maryland, United States., Suffredini AF; Clinical Center/Critical Care Medicine Department, National Institutes of Health, Bethesda, Maryland, United States., Solomon MA; Clinical Center/Critical Care Medicine Department, National Institutes of Health, Bethesda, Maryland, United States., Elinoff JM; Clinical Center/Critical Care Medicine Department, National Institutes of Health, Bethesda, Maryland, United States., Danner RL; Clinical Center/Critical Care Medicine Department, National Institutes of Health, Bethesda, Maryland, United States. |
| Abstrakt: |
NR2F2 is expressed in endothelial cells (ECs) and Nr2f2 knockout produces lethal cardiovascular defects. In humans, reduced NR2F2 expression is associated with cardiovascular diseases including congenital heart disease and atherosclerosis. Here, NR2F2 silencing in human primary ECs led to inflammation, endothelial-to-mesenchymal transition (EndMT), proliferation, hypermigration, apoptosis-resistance, and increased production of reactive oxygen species. These changes were associated with STAT and AKT activation along with increased production of DKK1. Co-silencing DKK1 and NR2F2 prevented NR2F2-loss-induced STAT and AKT activation and reversed EndMT. Serum DKK1 concentrations were elevated in patients with pulmonary arterial hypertension (PAH) and DKK1 was secreted by ECs in response to in vitro loss of either BMPR2 or CAV1, which are genetic defects associated with the development of PAH. In human primary ECs, NR2F2 suppressed DKK1, whereas its loss conversely induced DKK1 and disrupted endothelial homeostasis, promoting phenotypic abnormalities associated with pathologic vascular remodeling. Activating NR2F2 or blocking DKK1 may be useful therapeutic targets for treating chronic vascular diseases associated with EC dysfunction. NEW & NOTEWORTHY NR2F2 loss in the endothelial lining of blood vessels is associated with cardiovascular disease. Here, NR2F2 -silenced human endothelial cells were inflammatory, proliferative, hypermigratory, and apoptosis-resistant with increased oxidant stress and endothelial-to-mesenchymal transition. DKK1 was induced in NR2F2 -silenced endothelial cells, while co-silencing NR2F2 and DKK1 prevented NR2F2-loss-associated abnormalities in endothelial signaling and phenotype. Activating NR2F2 or blocking DKK1 may be useful therapeutic targets for treating vascular diseases associated with endothelial dysfunction. |
