PDF(Pubmed)
Abstract：
The aortic root is the predominant site for development of aneurysm caused by heterozygous loss-of-function mutations in positive effectors of the transforming growth factor-β (TGF-β) pathway. Using a mouse model of Loeys-Dietz syndrome (LDS) that carries a heterozygous kinase-inactivating mutation in TGF-β receptor I, we found that the effects of this mutation depend on the lineage of origin of vascular smooth muscle cells (VSMCs). Secondary heart field-derived (SHF-derived), but not neighboring cardiac neural crest-derived (CNC-derived), VSMCs showed impaired Smad2/3 activation in response to TGF-β, increased expression of angiotensin II (AngII) type 1 receptor (Agtr1a), enhanced responsiveness to AngII, and higher expression of TGF-β ligands. The preserved TGF-β signaling potential in CNC-derived VSMCs associated, in vivo, with increased Smad2/3 phosphorylation. CNC-, but not SHF-specific, deletion of Smad2 preserved aortic wall architecture and reduced aortic dilation in this mouse model of LDS. Taken together, these data suggest that aortic root aneurysm predisposition in this LDS mouse model depends both on defective Smad signaling in SHF-derived VSMCs and excessive Smad signaling in CNC-derived VSMCs. This work highlights the importance of considering the regional microenvironment and specifically lineage-dependent variation in the vulnerability to mutations in the development and testing of pathogenic models for aortic aneurysm.
摘要：
主动脉根是由转化生长因子-β（TGF-β）途径的正效应子的杂合功能丧失突变引起的动脉瘤发展的主要部位。使用Loeys-Dietz综合征（LDS）的小鼠模型，该模型在TGF-β受体I中携带杂合激酶失活突变，我们发现这种突变的作用取决于血管平滑肌细胞(VSMC)的起源谱系.次级心脏场衍生（SHF衍生），但不是邻近的心脏神经峰衍生（CNC衍生），VSMC显示对TGF-β的Smad2/3激活受损，血管紧张素II（AngII）1型受体（Agtr1a）的表达增加，增强对AngII的反应能力，和TGF-β配体的较高表达。在CNC衍生的VSMC中保留的TGF-β信号传导电位相关，在体内，Smad2/3磷酸化增加。CNC-,但不是SHF特定的，在该LDS小鼠模型中，Smad2的缺失保留了主动脉壁结构并减少了主动脉扩张。一起来看,这些数据表明,在LDS小鼠模型中,主动脉根部动脉瘤的易感性既取决于SHF衍生的VSMC中Smad信号的缺陷,也取决于CNC衍生的VSMC中Smad信号的过度.这项工作强调了在主动脉瘤致病模型的开发和测试中，考虑区域微环境，特别是谱系依赖性变异对突变的脆弱性的重要性。
