Endothelial Loss of ETS1 Impairs Coronary Vascular Development and Leads to Ventricular Non-Compaction.
Endothelial Loss of ETS1 Impairs Coronary Vascular Development and Leads to Ventricular Non-Compaction.
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DOI：
10.1161/circresaha.121.319955
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发表时间：
2022-08-19
影响因子：
20.1
通讯作者：
Grossfeld, Paul
中科院分区：
文献类型：
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作者：
Wang, Lu;Lin, Lizhu;Qi, Hui;Chen, Ju;Grossfeld, Paul
雅各布森综合征（JBS）是一种罕见的染色体疾病，由人类11号染色体长臂缺失引起，导致多种发育缺陷，包括先天性心脏病（CHD）。对人类和基因工程小鼠的联合研究表明，ETS 1的缺失是JBS中CHDs的原因，但潜在的分子和细胞机制尚不清楚。确定ETS 1在心脏发育中的作用，特别是其在冠状动脉内皮和内皮细胞中的作用，以及ETS 1缺失导致冠状动脉血管缺陷和心室致密化不全的机制。使用ETS 1全局和内皮特异性敲除小鼠。表型评估，RNA测序和染色质免疫沉淀分析与表达分析，免疫荧光和RNAscope原位杂交一起进行，以揭示表型和转录组的变化，响应于损失的ETS 1。内皮细胞中ETS 1的缺失导致心室致密化不全，再现了ETS 1整体缺失引起的表型。ETS 1的内皮特异性缺失降低了Alk 1、Cldn 5、Sox 18、Robo 4、Esm 1和Kdr（内皮细胞中六个重要的血管生成相关基因）的水平，导致与致密带心肌细胞增殖降低相关的冠状动脉血管发育缺陷。由于ETS 1的缺失，ALK 1在内皮细胞中的表达下调，沿着TGFβ1和TGFβ3的上调，伴随着小梁层中TGFBR 2/TGFBR 1/SMAD 2信号传导的增加和细胞外基质（ECM）表达的增加，与小梁心肌细胞增殖的增加相关。这些结果证明了内皮和内皮细胞ETS 1在心脏发育中的重要性。描述心脏发育中涉及ETS 1的基因调控网络将增强我们对心室和冠状动脉血管发育缺陷的分子机制的理解，并将导致先天性心脏病患者治疗方法的改进。
Jacobsen syndrome (JBS) is a rare chromosomal disorder caused by deletions in the long arm of human chromosome 11, resulting in multiple developmental defects including congenital heart defects (CHDs). Combined studies in humans and genetically engineered mice implicate that loss of ETS1 is the cause of CHDs in JBS, but the underlying molecular and cellular mechanisms are unknown. To determine the role of ETS1 in heart development, specifically its roles in coronary endothelium and endocardium and the mechanisms by which loss of ETS1 causes coronary vascular defects and ventricular non-compaction. ETS1 global and endothelial-specific knockout mice were used. Phenotypic assessments, RNA sequencing and chromatin immunoprecipitation analysis were performed together with expression analysis, immunofluorescence and RNAscope in situ hybridization to uncover phenotypic and transcriptomic changes in response to loss of ETS1. Loss of ETS1 in endothelial cells causes ventricular non-compaction, reproducing the phenotype arising from global deletion of ETS1. Endothelial-specific deletion of ETS1 decreased the levels of Alk1, Cldn5, Sox18, Robo4, Esm1 and Kdr, six important angiogenesis-relevant genes in endothelial cells, causing a coronary vasculature developmental defect in association with decreased compact zone cardiomyocyte proliferation. Down-regulation of ALK1 expression in endocardium due to the loss of ETS1, along with the up-regulation of TGFβ1 and TGFβ3, occurred with increased TGFBR2/TGFBR1/SMAD2 signaling and increased extracellular matrix (ECM) expression in the trabecular layer, in association with increased trabecular cardiomyocyte proliferation. These results demonstrate the importance of endothelial and endocardial ETS1 in cardiac development. Delineation of the gene regulatory network involving ETS1 in heart development will enhance our understanding of the molecular mechanisms underlying ventricular and coronary vascular developmental defects, and will lead to improved approaches for the treatment of patients with congenital heart disease.