BMPR2型
医学
肺动脉高压
胚胎血管重塑
下调和上调
骨形态发生蛋白
内皮
缺氧(环境)
转化生长因子
癌症研究
内科学
化学
基因
生物化学
有机化学
氧气
作者
Ann Reynolds,Mark Holmes,Sergei M. Danilov,Paul N. Reynolds
出处
期刊:The European respiratory journal
[European Respiratory Society]
日期:2011-07-07
卷期号:39 (2): 329-343
被引量:154
标识
DOI:10.1183/09031936.00187310
摘要
Pulmonary arterial hypertension (PAH) remains a fatal disease despite modern pharmacotherapy. Mutations in the gene for bone morphogenetic protein receptor type II (BMPR2) lead to reduced BMPR2 expression, which is causally linked to PAH. BMPR2 is predominantly expressed on pulmonary endothelium and has complex interactions with transforming growth factor (TGF)-β signalling mechanisms. Our objectives were to assess the effect on PAH of upregulating BMPR2 by targeted adenoviral BMPR2 gene delivery to the pulmonary vascular endothelium. We used two established rat models of PAH: chronic hypoxia and monocrotaline (MCT). In both hypertensive models, those receiving BMPR2 had less right ventricular hypertrophy, less pulmonary vascular resistance, improved cardiac function and reduced vascular remodelling. In the MCT model, there was an increase in TGF-β, which was prevented by BMPR2 treatment. In vitro, TGF-β1-induced endothelial-mesenchymal transition (EndMT) in human pulmonary microvascular endothelial cells, which was associated with reduced BMPR2 expression. EndMT was partially ameliorated by stimulating BMPR2 signalling with appropriate ligands even in the ongoing presence of TGF-β1. Collectively, these results indicate therapeutic potential for upregulation of the BMPR2 axis in PAH, which may be, in part, mediated by countering the remodelling effects of TGF-β.
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