Endothelial plasticity drives aberrant vascularization and impedes cardiac repair after myocardial infarction.
Endothelial plasticity drives aberrant vascularization and impedes cardiac repair after myocardial infarction.
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内皮可塑性驱动异常血管化并阻碍心肌梗塞后心脏修复。
DOI：
10.1038/s44161-022-00047-3
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发表时间：
2022-04
期刊：
影响因子：
--
通讯作者：
Gong, Yanqing
中科院分区：
文献类型：
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作者：
Huang, Menggui;Yang, Fan;Zhang, Duo;Lin, Maohuan;Duan, Hao;El-Mayta, Rakan;Zhang, Lin;Qin, Ling;Shewale, Swapnil V;Pei, Liming;Mitchell, Michael J;Rader, Daniel J;Fan, Yi;Gong, Yanqing
心肌梗死（MI）是全世界死亡的主要原因，很大程度上是因为目前缺乏有效的干预措施来恢复心肌梗死后的心脏功能。在这里，我们描述了 MI 引起的血管异常，并提出以获得性内皮细胞 (EC) 变化为目标，以使血管正常化并促进 MI 后的心脏修复。 MI 相关 EC 的单细胞转录组分析表明，EC 获得间充质基因特征，导致表型和功能变化并导致血管异常。我们发现PDGF/NF-κB/HIF-1α轴在缺氧条件下诱导ECs中Snail表达和间充质表型，从而导致异常血管化。 EC 特异性敲除 PDGFR-β、药理学 PDGFR 抑制或基于纳米颗粒的靶向 PDGFR-β siRNA 递送小鼠可减轻梗塞组织中的血管异常并改善 MI 后的心脏修复。这些发现说明了控制缺血后异常新生血管形成的机制，并表明针对 PDGF/Snail 介导的内皮可塑性可能为脉管系统正常化和治疗缺血性心脏病提供机会。黄等人。研究表明，心肌梗死相关的脉管系统在结构和功能上都存在异常，这会阻碍小鼠的血管功能和心脏修复。对 MI 后心脏内皮转录组的分析确定了负责内皮细胞间充质转化的 PDGF/NF-kB/HIF-1a/Snail 轴，并表明 PDGF 信号传导的基因消融或靶向破坏可使脉管系统正常化并改善 MI 后心脏功能的恢复。
Myocardial infarction (MI) is a leading cause of death worldwide, largely because efficient interventions to restore cardiac function after MI are currently lacking. Here, we characterize vascular aberrancies induced by MI, and propose to target acquired endothelial cell (EC) changes to normalize vessels and promote cardiac repair after MI. Single-cell transcriptome analyses of MI-associated ECs indicates that ECs acquire mesenchymal gene signature that result in phenotypic and functional changes and lead to vessel abnormalities. We identify a PDGF/NF-κB/HIF-1α axis that induces Snail expression and mesenchymal phenotypes in ECs under hypoxia, altogether causing aberrant vascularization. EC-specific knockout of PDGFR-β, pharmacological PDGFR inhibition or nanoparticle-based targeted PDGFR-β siRNA delivery in mice attenuates vascular abnormalities in the infarcted tissue and improves cardiac repair after MI. These findings illustrate a mechanism controlling aberrant neovascularization after ischemia, and suggest that targeting PDGF/Snail-mediated endothelial plasticity may offer opportunities for normalizing vasculature and treating ischemic heart diseases. Huang et al. show that MI-associated vasculature is structurally and functionally abnormal, which impedes vessel function and cardiac repair in mice. Analyses of the transcriptome of the cardiac endothelium after MI identify a PDGF/NF-kB/HIF-1a/Snail axis responsible for mesenchymal transformation of endothelial cells, and show that genetic ablation or targeted disruption of PDGF signaling normalizes vasculature and improves cardiac function recovery after MI.