Second Heart Field-Derived Cells Contribute to Angiotensin II-Mediated Ascending Aortopathies.
Second Heart Field-Derived Cells Contribute to Angiotensin II-Mediated Ascending Aortopathies.
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第二心脏场来源的细胞促成血管紧张素II介导的升主动脉病变。
DOI：
10.1161/circulationaha.121.058173
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发表时间：
2022-03-29
期刊：
影响因子：
37.8
通讯作者：
Daugherty, Alan
中科院分区：
文献类型：
--
作者：
Sawada, Hisashi;Katsumata, Yuriko;Higashi, Hideyuki;Zhang, Chen;Li, Yanming;Morgan, Stephanie;Lee, Lang H.;Singh, Sasha A.;Chen, Jeff Z.;Franklin, Michael K.;Moorleghen, Jessica J.;Howatt, Deborah A.;Rateri, Debra L.;Shen, Ying H.;LeMaire, Scott A.;Aikawa, Masanori;Majesky, Mark W.;Lu, Hong S.;Daugherty, Alan
升主动脉是动脉瘤和夹层的常见部位。该主动脉区域由中膜和外膜细胞镶嵌而成，这些细胞胚胎性地来源于第二心脏野（SHF）或心脏神经嵴。SHF衍生的细胞填充与胸部病变的空间特异性相一致的区域。本研究的目的是确定SHF衍生细胞是否以及如何促进上行性前列腺病变。在散发性胸部病变患者和血管紧张素II（AngII）输注小鼠中检查升主动脉病变。没有明显的病理学从AngII输注小鼠的上行动脉瘤进行质谱辅助蛋白质组学，并通过单细胞转录组学分析确定SHF衍生细胞的分子特征。在SHF衍生的细胞中进行低密度脂蛋白受体相关蛋白1（Lrp 1）或转化生长因子-β受体2（Tgfbr 2）的遗传缺失，以检查SHF衍生的细胞对血管完整性的影响。人升主动脉瘤组织的病理主要发生在外中层和外膜。这种梯度在AngII输注后的小鼠睾丸中被模拟，这与SHF衍生细胞的分布一致。蛋白质组学表明，短暂的血管紧张素II输液，明显的病理学，诱发SMC蛋白和细胞外基质蛋白，包括几个LRP 1配体的差异表达下调。SHF衍生细胞中LRP 1缺失增加AngII诱导的升主动脉瘤和破裂。单细胞转录组学分析显示，短暂的血管紧张素II输注降低Lrp 1和Tgfbr 2 mRNA丰度的SHF衍生细胞，并诱导一个独特的成纤维细胞群体与低丰度的Tgfbr 2 mRNA。SHF特异性Tgfbr 2缺失导致E12.5胚胎死亡，伴随流出道扩张和腹膜后出血。整合蛋白质组学和单细胞转录组学的结果确定纤溶酶原激活物抑制剂1（PAI 1）作为SHF衍生的SMC和成纤维细胞在AngII输注过程中增加最多的蛋白质。免疫染色显示PAI 1在AngII输注小鼠和人类升支血管平滑肌瘤的升支血管中均存在跨壁梯度，其模拟了中膜和外膜病理的梯度。SHF衍生的细胞通过与主动脉PAI 1增加相关的LRP 1和TGF-β信号传导在维持血管完整性中发挥关键作用。
The ascending aorta is a common location for aneurysm and dissection. This aortic region is populated by a mosaic of medial and adventitial cells that are embryonically derived from either the second heart field (SHF) or the cardiac neural crest. SHF-derived cells populate areas that coincide with the spatial specificity of thoracic aortopathies. The purpose of this study was to determine whether and how SHF-derived cells contribute to ascending aortopathies. Ascending aortic pathologies were examined in patients with sporadic thoracic aortopathies and angiotensin II (AngII)-infused mice. Ascending aortas without overt pathology from AngII-infused mice were subjected to mass spectrometry assisted proteomics, and molecular features of SHF-derived cells were determined by single cell transcriptomic analyses. Genetic deletion of either low-density lipoprotein receptor-related protein 1 (Lrp1) or transforming growth factor-β receptor 2 (Tgfbr2) in SHF-derived cells was conducted to examine the impact of SHF-derived cells on vascular integrity. Pathologies in human ascending aortic aneurysmal tissues were predominant in outer medial layers and adventitia. This gradient was mimicked in mouse aortas following AngII infusion that was coincident with the distribution of SHF-derived cells. Proteomics indicated that brief AngII infusion, prior to overt pathology, evoked downregulation of SMC proteins and differential expression of extracellular matrix proteins, including several LRP1 ligands. LRP1 deletion in SHF-derived cells augmented AngII-induced ascending aortic aneurysm and rupture. Single cell transcriptomic analysis revealed that brief AngII infusion decreased Lrp1 and Tgfbr2 mRNA abundance in SHF-derived cells and induced a unique fibroblast population with low abundance of Tgfbr2 mRNA. SHF-specific Tgfbr2 deletion led to embryonic lethality at E12.5 with dilatation of the outflow tract and retroperitoneal hemorrhage. Integration of proteomic and single cell transcriptomics results identified plasminogen activator inhibitor 1 (PAI1) as the most increased protein in SHF-derived SMCs and fibroblasts during AngII infusion. Immunostaining revealed a transmural gradient of PAI1 in both ascending aortas of AngII-infused mice and human ascending aneurysmal aortas that mimicked the gradient of medial and adventitial pathologies. SHF-derived cells exert a critical role in maintaining vascular integrity through LRP1 and TGF-β signaling associated with increases of aortic PAI1.
影响因子：
3.7
作者：
Basford JE;Koch S;Anjak A;Singh VP;Krause EG;Robbins N;Weintraub NL;Hui DY;Rubinstein J
通讯作者：
Rubinstein J