Preferential uptake of SARS-CoV-2 by pericytes potentiates vascular damage and permeability in an organoid model of the microvasculature.

ABSTRACT:

Aims

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.

Methods and results

Immunofluorescence of post-mortem patient sections were used to assess pathophysiological aspects of COVID19 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 ACE2 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 NOTCH3, angiopoietin-2 and TEK. Activation of vascular organoids with IL-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 VWF deposition in the capillaries of these patients, with thrombi in large vessels rich in VWF and fibrin.

Conclusions

Together our data indicates that direct viral exposure to the microvasculature modelled by organoid infection and viral antigen treatment result 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.

Translational perspective

Endotheliitis is a serious complication of severe COVID-19 patients which remains poorly understood. We identify a pericyte mediated mechanism by which the vasculature becomes compromised, contributing to thrombotic complications, highlighting important avenues for the development of therapies.

SUBMITTER: Khan AO 

PROVIDER: S-EPMC9214165 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature