Preferential uptake of SARS-CoV-2 by pericytes potentiates vascular damage and permeability in an organoid model of the microvasculature.
Preferential uptake of SARS-CoV-2 by pericytes potentiates vascular damage and permeability in an organoid model of the microvasculature.
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DOI：
10.1093/cvr/cvac097
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发表时间：
2022-12-09
影响因子：
10.8
通讯作者：
中科院分区：
文献类型：
--
作者：
血栓性并发症和血管病变与严重的COVID-19感染广泛相关;然而，诱导内皮炎和微循环中内皮完整性破坏的机制知之甚少。我们假设在血管壁内，周细胞优先摄取病毒颗粒并介导随后的血管完整性丧失。尸检患者切片的免疫荧光被用于评估COVID-19感染的病理生理学方面。使用暴露于活病毒颗粒或重组病毒抗原的血管类器官模型评估COVID-19对微血管系统的影响。我们发现，与血管内皮细胞相比，病毒进入受体血管紧张素转换酶2在周细胞上的表达增加，连接蛋白CD 144的表达减少，以及用活病毒和/或病毒抗原治疗后细胞死亡增加。我们观察到与血管通透性有关的基因失调，包括Notch受体3、血管生成素-2和TEK。用白细胞介素-1 β激活血管类器官对血管通透性没有累加效应。在一些患者的肺周细胞中检测到刺突抗原，这与这些患者的毛细血管中的CD 144表达减少、血小板募集增加和血管性血友病因子（VWF）沉积增加相关，并且在富含VWF和纤维蛋白的大血管中存在血栓。总之，我们的数据表明，直接病毒暴露于由类器官感染和病毒抗原治疗建模的微血管系统导致周细胞感染、脱离、损伤和细胞死亡，破坏周细胞-内皮细胞串扰并增加微血管内皮通透性，这可以促进微循环中的血栓形成和出血并发症。SARS-CoV-2感染周细胞会增加血管损伤和渗透性。周细胞优先摄取SARS-CoV-2诱导其凋亡，导致内皮细胞连接和血管网络破坏，促进血管通透性。SARS-CoV-2介导的内皮病变与COVID-19患者的血栓并发症相关。
Thrombotic complications and vasculopathy have been extensively associated with severe COVID-19 infection; however, the mechanisms inducing endotheliitis and the disruption of endothelial integrity in the microcirculation are poorly understood. We hypothesized that within the vessel wall, pericytes preferentially take up viral particles and mediate the subsequent loss of vascular integrity. Immunofluorescence of post-mortem patient sections was used to assess pathophysiological aspects of COVID-19 infection. The effects of COVID-19 on the microvasculature were assessed using a vascular organoid model exposed to live viral particles or recombinant viral antigens. We find increased expression of the viral entry receptor angiotensin-converting enzyme 2 on pericytes when compared to vascular endothelium and a reduction in the expression of the junctional protein CD144, as well as increased cell death, upon treatment with both live virus and/or viral antigens. We observe a dysregulation of genes implicated in vascular permeability, including Notch receptor 3, angiopoietin-2, and TEK. Activation of vascular organoids with interleukin-1β did not have an additive effect on vascular permeability. Spike antigen was detected in some patients’ lung pericytes, which was associated with a decrease in CD144 expression and increased platelet recruitment and von Willebrand factor (VWF) deposition in the capillaries of these patients, with thrombi in large vessels rich in VWF and fibrin. Together, our data indicate that direct viral exposure to the microvasculature modelled by organoid infection and viral antigen treatment results in pericyte infection, detachment, damage, and cell death, disrupting pericyte-endothelial cell crosstalk and increasing microvascular endothelial permeability, which can promote thrombotic and bleeding complications in the microcirculation. Pericyte infection by SARS-CoV-2 increases vascular damage and permeability. Preferential uptake of SARS-CoV-2 by pericytes induces their apoptosis leading to the disruption of endothelial cell junctions and the vascular network promoting vascular permeability. SARS-CoV-2-mediated endotheliopathy is associated with thrombotic complications in patients with COVID-19.
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