PDF(Pubmed)
Abstract：
Components of bone morphogenetic protein (BMP) signalling have been implicated in both pathogenesis of pulmonary arterial hypertension (PAH) and endothelial-mesenchymal transition (EndoMT). In particular, the importance of BMP type 2 receptor in these processes has been extensively analysed. However, the contribution of BMP type 1 receptors (BMPR1s) to the onset of PAH and EndoMT remains poorly understood. BMPR1A, one of BMPR1s, was recently implicated in the pathogenesis of PAH, and was found to be down-regulated in the lungs of PAH patients, neither the downstream mechanism nor its contribution to EndoMT has been described. Therefore, we aim to delineate the role of endothelial BMPR1A in modulating EndoMT and pathogenesis of PAH.
We find that BMPR1A knockdown in endothelial cells (ECs) induces hallmarks of EndoMT, and deletion of endothelial Bmpr1a in adult mice (Bmpr1aiECKO) leads to development of PAH-like symptoms due to excessive EndoMT. By lineage tracing, we show that endothelial-derived smooth muscle cells are increased in endothelial Bmpr1a-deleted mice. Mechanistically, we identify ZEB1 as a primary target for BMPR1A in this setting; upon BMPR1A activation, ID2 physically interacts and sequesters ZEB1 to attenuate transcription of Tgfbr2, which in turn lowers the responses of ECs towards transforming growth factor beta (TGFβ) stimulation and prevents excessive EndoMT. In Bmpr1aiECKO mice, administering endothelial targeting lipid nanoparticles containing siRNA against Tgfbr2 effectively ameliorate PAH, reiterating the importance of BMPR1A-ID2/ZEB1-TGFBR2 axis in modulating progression of EndoMT and pathogenesis of PAH.
We demonstrate that BMPR1A is key to maintain endothelial identity and to prevent excessive EndoMT. We identify BMPR1A-induced interaction between ID2 and ZEB1 is the key regulatory step for onset of EndoMT and pathogenesis of PAH. Our findings indicate that BMPR1A-ID2/ZEB1-TGFBR2 signalling axis could serve as a potential novel therapeutic target for PAH and other EndoMT-related vascular disorders.
We find that BMPR1A knockdown in endothelial cells (ECs) induces hallmarks of EndoMT, and deletion of endothelial Bmpr1a in adult mice (Bmpr1aiECKO) leads to development of PAH-like symptoms due to excessive EndoMT. By lineage tracing, we show that endothelial-derived smooth muscle cells are increased in endothelial Bmpr1a-deleted mice. Mechanistically, we identify ZEB1 as a primary target for BMPR1A in this setting; upon BMPR1A activation, ID2 physically interacts and sequesters ZEB1 to attenuate transcription of Tgfbr2, which in turn lowers the responses of ECs towards transforming growth factor beta (TGFβ) stimulation and prevents excessive EndoMT. In Bmpr1aiECKO mice, administering endothelial targeting lipid nanoparticles containing siRNA against Tgfbr2 effectively ameliorate PAH, reiterating the importance of BMPR1A-ID2/ZEB1-TGFBR2 axis in modulating progression of EndoMT and pathogenesis of PAH.
We demonstrate that BMPR1A is key to maintain endothelial identity and to prevent excessive EndoMT. We identify BMPR1A-induced interaction between ID2 and ZEB1 is the key regulatory step for onset of EndoMT and pathogenesis of PAH. Our findings indicate that BMPR1A-ID2/ZEB1-TGFBR2 signalling axis could serve as a potential novel therapeutic target for PAH and other EndoMT-related vascular disorders.
摘要：
目的：BMP信号的组成部分与肺动脉高压（PAH）和内皮-间质转化（EndoMT）的发病机制有关。特别是,已经广泛分析了BMP2型受体(BMPR2)在这些过程中的重要性。然而,BMP1型受体（BMPR1s）对PAH和EndoMT发病的贡献仍然知之甚少。BMPR1A,BMPR1之一，最近与PAH的发病机制有关，并被发现在PAH患者的肺部下调，既没有描述下游机制，也没有描述其对EndoMT的贡献。因此,我们旨在描述内皮BMPR1A在调节EndoMT和PAH发病机制中的作用。
结果：我们发现内皮细胞（ECs）中的BMPR1A敲低可诱导EndoMT的标志，成年小鼠（Bmpr1aiECKO）中内皮Bmpr1a的缺失导致由于过度的EndoMT而导致PAH样症状的发展。通过血统追踪，我们显示内皮来源的平滑肌细胞在内皮Bmpr1a缺失小鼠中增加。机械上,在此设置中，我们将ZEB1识别为BMPR1A的主要目标；在BMPR1A激活后，ID2在物理上相互作用并隔离ZEB1以减弱Tgfbr2的转录，从而降低EC对TGF-β刺激的反应并防止过度的EndoMT。在Bmpr1aiECKO小鼠中，施用含有针对Tgfbr2的siRNA的内皮靶向脂质纳米粒有效改善PAH，重申BMPR1A-ID2/ZEB1-TGFBR2轴在调节EndoMT进展和PAH发病机制中的重要性。
结论：我们证明BMPR1A是维持内皮特性和防止过度EndoMT的关键。我们确定BMPR1A诱导的ID2和ZEB1之间的相互作用是EndoMT发作和PAH发病机理的关键调节步骤。我们的发现表明，BMPR1A-ID2/ZEB1-TGFBR2信号轴可以作为PAH和其他EndoMT相关血管疾病的潜在新治疗靶标。
结果：我们发现内皮细胞（ECs）中的BMPR1A敲低可诱导EndoMT的标志，成年小鼠（Bmpr1aiECKO）中内皮Bmpr1a的缺失导致由于过度的EndoMT而导致PAH样症状的发展。通过血统追踪，我们显示内皮来源的平滑肌细胞在内皮Bmpr1a缺失小鼠中增加。机械上,在此设置中，我们将ZEB1识别为BMPR1A的主要目标；在BMPR1A激活后，ID2在物理上相互作用并隔离ZEB1以减弱Tgfbr2的转录，从而降低EC对TGF-β刺激的反应并防止过度的EndoMT。在Bmpr1aiECKO小鼠中，施用含有针对Tgfbr2的siRNA的内皮靶向脂质纳米粒有效改善PAH，重申BMPR1A-ID2/ZEB1-TGFBR2轴在调节EndoMT进展和PAH发病机制中的重要性。
结论：我们证明BMPR1A是维持内皮特性和防止过度EndoMT的关键。我们确定BMPR1A诱导的ID2和ZEB1之间的相互作用是EndoMT发作和PAH发病机理的关键调节步骤。我们的发现表明，BMPR1A-ID2/ZEB1-TGFBR2信号轴可以作为PAH和其他EndoMT相关血管疾病的潜在新治疗靶标。
