Lineage-specific events underlie aortic root aneurysm pathogenesis in Loeys-Dietz syndrome
Lineage-specific events underlie aortic root aneurysm pathogenesis in Loeys-Dietz syndrome
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DOI：
10.1172/jci123547
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发表时间：
2019-02-01
影响因子：
15.9
通讯作者：
Dietz, Harry C.
中科院分区：
文献类型：
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作者：
MacFarlane, Elena Gallo;Parker, Sarah J.;Dietz, Harry C.
主动脉根部是由转化生长因子-β (TGF-β) 途径正效应子的杂合功能丧失突变引起的动脉瘤形成的主要部位。使用携带 TGF-β 受体 I 杂合激酶失活突变的 Loeys-Dietz 综合征 (LDS) 小鼠模型，我们发现该突变的影响取决于血管平滑肌细胞 (VSMC) 的起源谱系。次级心野来源（SHF 来源）而非邻近心脏神经嵴来源（CNC 来源）的 VSMC 表现出响应 TGF-β 的 Smad2/3 激活受损、血管紧张素 II (AngII) 1 型受体 (Agtr1a) 表达增加、对 AngII 的反应性增强以及 TGF-β 配体表达较高。 CNC 衍生的 VSMC 中保留的 TGF-β 信号传导潜力在体内与 Smad2/3 磷酸化增加相关。在 LDS 小鼠模型中，CNC 特异性（而非 SHF 特异性）删除 Smad2 可保留主动脉壁结构并减少主动脉扩张。综上所述，这些数据表明，LDS 小鼠模型中主动脉根部动脉瘤的易感性取决于 SHF 衍生的 VSMC 中的缺陷 Smad 信号传导和 CNC 衍生的 VSMC 中的过度 Smad 信号传导。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以及特别是谱系依赖性变异对突变脆弱性的重要性。
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-beta (TGF-beta) pathway. Using a mouse model of Loeys-Dietz syndrome (LDS) that carries a heterozygous kinase-inactivating mutation in TGF-beta 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-beta, increased expression of angiotensin II (AngII) type 1 receptor (Agtr1a), enhanced responsiveness to AngII, and higher expression of TGF-beta ligands. The preserved TGF-beta 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.