Endothelial-Mesenchymal Transition in Cardiovascular Disease.
Endothelial-Mesenchymal Transition in Cardiovascular Disease.
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心血管疾病中的内皮-间质转化。
DOI：
10.1161/atvbaha.121.313788
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发表时间：
2021-09
期刊：
影响因子：
--
通讯作者：
Bischoff J
中科院分区：
文献类型：
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作者：
Alvandi Z;Bischoff J
内皮细胞向间充质细胞转化（EndMT）是内皮细胞抑制内皮细胞成分特性并呈现间充质细胞行为的动态过程。在这一过程的开始，内皮细胞松开它们的细胞-细胞连接，降解基底膜并迁移到血管周围环境中。这些初始内皮行为反映了细胞表型的瞬时调节，即，表型调节，有时称为部分EndMT。内皮连接的松弛和迁移也见于炎症和血管生成环境中，使得起始EndMT的内皮细胞具有与响应炎症信号或发芽以形成新血管的内皮细胞重叠的行为和基因表达。减少内皮连接增加渗透性，这有利于白细胞运输，而内皮迁移先于血管生成萌芽和新血管形成;随着炎症和血管生成刺激消退，内皮屏障和静止都恢复。完全EndMT的进展超出了表型调节，使得间充质特征变得突出，内皮功能减弱。在促适应、再生环境中，新的间充质细胞产生细胞外基质并有助于组织完整性，而在适应不良、病理环境中，新的间充质细胞变得纤维化，过度产生基质，导致组织僵硬，最终影响功能。在这里，我们将审查什么是已知的转化生长因子β（TGFβ）如何影响这一连续体从连接松动到细胞迁移及其相关性心血管疾病。TGFβ1-3和Wnt信号启动EndMT，而层流剪切应力诱导的ERK 5和KLF 2/4沿着FGFR 1和BMPR 2信号阻止EndMT。乙酰辅酶A通过增强脂肪酸氧化，也使EndMT最小化。EndMT过程中内皮细胞形态发生显著变化，因为转录因子Snail 1和Slug抑制内皮基因并增加间充质基因。
Endothelial-to-mesenchymal transition (EndMT) is a dynamic process in which endothelial cells suppress constituent endothelial properties and take on mesenchymal cell behaviors. To begin the process, endothelial cells loosen their cell-cell junctions, degrade the basement membrane and migrate out into the perivascular surroundings. These initial endothelial behaviors reflect a transient modulation of cellular phenotype, i.e., a phenotypic modulation, that is sometimes referred to as partial EndMT. Loosening of endothelial junctions and migration are also seen in inflammatory and angiogenic settings such that endothelial cells initiating EndMT have overlapping behaviors and gene expression with endothelial cells responding to inflammatory signals or sprouting to form new blood vessels. Reduced endothelial junctions increases permeability, which facilitates leukocyte trafficking, while endothelial migration precedes angiogenic sprouting and neovascularization; both endothelial barriers and quiescence are restored as inflammatory and angiogenic stimuli subside. Complete EndMT proceeds beyond phenotypic modulation such that mesenchymal characteristics become prominent and endothelial functions diminish. In pro-adaptive, regenerative settings the new mesenchymal cells produce extracellular matrix and contribute to tissue integrity whereas in mal-adaptive, pathologic settings the new mesenchymal cells become fibrotic, overproducing matrix to cause tissue stiffness, which eventually impacts function. Here we will review what is known about how transforming growth factor beta (TGFβ) influences this continuum from junctional loosening to cellular migration and its relevance to cardiovascular diseases. TGFβ1-3 and Wnt signaling initiate EndMT while laminar shear stress-induced ERK5 and KLF2/4 along with FGFR1 and BMPR2 signaling prevent EndMT. Acetyl CoA, by enhancing fatty acid oxidation, also minimizes EndMT. Endothelial cell morphology changes dramatically during EndMT as transcription factors Snail1 and Slug suppress endothelial genes and increase mesenchymal genes.