This article is part of Cardiology Advisor‘s coverage of AHA Scientific Sessions 2020.
Flow-dependent expression of angiotensin-converting enzyme-2 (ACE2) was found to be associated with the susceptibility of brain endothelial cells to be directly infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), according to study results presented at the American Heart Association (AHA) Scientific Sessions 2020, held virtually from November 13 to 17, 2020.
In this study, researchers isolated and analyzed endothelial cells from human brain using RNA sequencing. Human umbilical vein and human brain microvascular cells were cultured in monolayers and endothelialized within a vascular model of the middle cerebral artery achieved using 3-dimenional (3D) printing. Quantitative PCR and direct RNA hybridization were used to measure gene expression levels. Endothelial binding was measured by immunocytochemistry, with the use of recombinant SARS-CoV-2 S protein and S protein–containing liposomes.
mRNA levels of ACE2 were found to be low in human brain and monolayer endothelial cell cultures. Both gene expression and protein levels of ACE2 were found to increase with vessel size and flow rates in the vascular model. Expression of ACE2 was further increased by shear stress, and this increase mediated by flow was found to increase the susceptibility of brain endothelial cells to binding of SARS-CoV-2 spike protein.
In the vascular model, SARS-CoV-2 S protein-containing liposomes were present in endothelial cells of human umbilical vein and brain microvascular origin, but not in the monolayer cultures, indicating that ACE2 gene expression requires flow.
SARS-CoV-2 spike protein binding to brain endothelial cells triggered in these cells the expression of a set of 83 unique genes, including upregulation of genes involved in the complement system (C3), myeloid inflammation (CD163), and chemokine signaling (CCL8, CXCL8, CCL24).
“[C]ellular infection by encapsulated SARS-CoV-2 virus in the presence of shear stress would trigger a more robust gene expression profile that may further identify brain-specific pathways activated by SARS-CoV-2 that can inform our understanding of the cerebrovascular tropism and response to this novel and unique virus,” noted the researchers.
Kaneko N, Satta S, Komuro Y, et al. Flow-mediated susceptibility and molecular response of cerebral endothelia to SARS- AQ1 CoV-2 infection. Presented at: AHA Scientific Sessions 2020; November 13-17, 2020. Presentation 161.
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