Dissecting aortic aneurysm in Marfan syndrome is associated with losartan-sensitive transcriptomic modulation of aortic cells.
Dissecting aortic aneurysm in Marfan syndrome is associated with losartan-sensitive transcriptomic modulation of aortic cells.
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马凡综合征中的主动脉夹层动脉瘤与血管紧张素 II 受体拮抗剂氯沙坦敏感的主动脉细胞转录组调节有关。
DOI：
10.1172/jci.insight.168793
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发表时间：
2023-05-22
期刊：
影响因子：
8
通讯作者：
Ramirez, Francesco
中科院分区：
文献类型：
--
作者：
Sun, Yifei;Asano, Keiichi;Sedes, Lauriane;Cantalupo, Anna;Hansen, Jens;Iyengar, Ravi;Walsh, Martin J.;Ramirez, Francesco
为了改善我们对导致急性主动脉夹层的胸主动脉瘤（TAA）发病机制的有限理解，采用单细胞RNA测序（scRNA-seq）来描述最常见的马凡综合征（MFS）的良好表征的小鼠模型中主动脉细胞群的疾病相关转录组学变化。结果，仅在Fbn 1 mgR/mgR小鼠的主动脉中鉴定出2个离散的主动脉细胞亚群（SMC 3和EC 4）。SMC 3细胞高度表达与细胞外基质形成和一氧化氮信号传导相关的基因，而EC 4转录谱在平滑肌细胞（SMC）、成纤维细胞和免疫细胞相关基因中富集。轨迹分析预测SMC 3和EC 4之间的密切表型调节，因此将其作为离散的MFS-modulated（MFSmod）亚群一起分析。原位杂交诊断转录本定位MFSmod细胞在Fbn 1 mgR/mgR血管内膜。基于参考的数据集整合揭示了在人TAA中调节的MFSmod和SMC衍生的细胞簇之间的转录组相似性。与血管紧张素II I型受体（At 1 r）对TAA发展的贡献一致，在用At 1 r拮抗剂氯沙坦治疗的Fbn 1 mgr/mgR小鼠的主动脉中不存在MFSmod细胞。总之，我们的研究结果表明，主动脉细胞特性的离散动态变化与MFS小鼠TAA夹层和MFS患者主动脉夹层风险增加相关。
To improve our limited understanding of the pathogenesis of thoracic aortic aneurysm (TAA) that leads to acute aortic dissection, single-cell RNA sequencing (scRNA-seq) was employed to profile disease-relevant transcriptomic changes of aortic cell populations in a well-characterized mouse model of the most commonly diagnosed form of Marfan syndrome (MFS). As result, 2 discrete subpopulations of aortic cells (SMC3 and EC4) were identified only in the aorta of Fbn1mgR/mgR mice. SMC3 cells highly express genes related to extracellular matrix formation and nitric oxide signaling, whereas the EC4 transcriptional profile is enriched in smooth muscle cell (SMC), fibroblast, and immune cell–related genes. Trajectory analysis predicted close phenotypic modulation between SMC3 and EC4, which were therefore analyzed together as a discrete MFS-modulated (MFSmod) subpopulation. In situ hybridization of diagnostic transcripts located MFSmod cells at the intima of Fbn1mgR/mgR aortas. Reference-based data set integration revealed transcriptomic similarity between MFSmod- and SMC-derived cell clusters modulated in human TAA. Consistent with the angiotensin II type I receptor (At1r) contribution to TAA development, MFSmod cells were absent in the aorta of Fbn1mgR/mgR mice treated with the At1r antagonist losartan. Altogether, our findings indicate that a discrete dynamic alteration of aortic cell identity is associated with dissecting TAA in MFS mice and increased risk of aortic dissection in MFS patients.
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影响因子：
64.8
作者：
Cao, Junyue;Spielmann, Malte;Shendure, Jay
通讯作者：
Shendure, Jay
影响因子：
16.6
作者：
Zheng GX;Terry JM;Belgrader P;Ryvkin P;Bent ZW;Wilson R;Ziraldo SB;Wheeler TD;McDermott GP;Zhu J;Gregory MT;Shuga J;Montesclaros L;Underwood JG;Masquelier DA;Nishimura SY;Schnall-Levin M;Wyatt PW;Hindson CM;Bharadwaj R;Wong A;Ness KD;Beppu LW;Deeg HJ;McFarland C;Loeb KR;Valente WJ;Ericson NG;Stevens EA;Radich JP;Mikkelsen TS;Hindson BJ;Bielas JH
通讯作者：
Bielas JH
DOI：
10.1161/atvbaha.120.314670
发表时间：
2020-09-01
影响因子：
8.7
作者：
Pedroza, Albert J.;Tashima, Yasushi;Fischbein, Michael P.
通讯作者：
Fischbein, Michael P.
DOI：
10.1038/s41572-021-00298-7
发表时间：
2021-09-02
期刊：
Nature reviews. Disease primers
影响因子：
--
作者：
通讯作者：
--
影响因子：
37.8
作者：
Pan H;Xue C;Auerbach BJ;Fan J;Bashore AC;Cui J;Yang DY;Trignano SB;Liu W;Shi J;Ihuegbu CO;Bush EC;Worley J;Vlahos L;Laise P;Solomon RA;Connolly ES;Califano A;Sims PA;Zhang H;Li M;Reilly MP
通讯作者：
Reilly MP