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标题：Obstruction of Small Arterioles in Patients with Critical Limb Ischemia due to Partial Endothelial-to-Mesenchymal Transition
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作者：Jacqueline Chevalier ; Hao Yin ; John-Michael Arpino 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2020
卷号：23
期号：6
页码：1-31
DOI：10.1016/j.isci.2020.101251
语种：English
出版社：Elsevier
摘要：SummaryCritical limb ischemia (CLI) is a hazardous manifestation of atherosclerosis and treatment failure is common. Abnormalities in the arterioles might underlie this failure but the cellular pathobiology of microvessels in CLI is poorly understood. We analyzed 349 intramuscular arterioles in lower limb specimens from individuals with and without CLI. Arteriolar densities were 1.8-fold higher in CLI muscles. However, 33% of small (<20 μm) arterioles were stenotic and 9% were completely occluded. The lumens were closed by bulky, re-oriented endothelial cells expressing abundant N-cadherin that uniquely localized between adjacent and opposing endothelial cells. S100A4 and SNAIL1 were also expressed, supporting an endothelial-to-mesenchymal transition. SMAD2/3 was activated in occlusive endothelial cells and TGFβ1 was increased in the adjacent mural cells. These findings identify a microvascular closure process based on mesenchymal transitions in a hyper-TGFß environment that may, in part, explain the limited success of peripheral artery revascularization procedures.Graphical AbstractDisplay OmittedHighlights•Small arterioles in patients with critical limb ischemia can be narrowed or closed•Arteriolar occlusion is due to bulky endothelial cells•Bulky endothelial cells have partially transitioned to mesenchymal cells•Occlusive cells interlock laterally and apically via N-cadherin neo-adhesionsClinical Finding; Human Specimen; Pathophysiology