Role of endothelial cell receptors in the context of SARS-CoV-2 infection (COVID-19)

Abstract

Endothelial cell (EC) dysfunction contributes to COVID-19-associated vascular inflammation and coagulopathy, and the angiotensin-converting enzyme 2 (ACE2) receptor plays a role in EC dysfunction in COVID-19. To expand the understanding of the role of the ACE2 receptor relative to EC dysfunction, this review addresses (1) tissue distribution of the ACE2 protein and its mRNA expression in humans, (2) susceptibility of the capillary ECs to SARS-CoV-2 infection, and (3) the role of EC dysfunction relevant to ACE2 and nuclear factor-κB in COVID-19.

Keywords: ACE2 receptor; COVID-19; NF-κB pathway; SARS-CoV-2; endothelial activation; endothelial dysfunction; p38.

Figure 1.

Proposed nuclear factor-κB (NF-κB) pathway by which angiotensin-converting enzyme 2 (ACE2) receptors induce endothelial dysfunction in COVID-19. The balance of NF-kB and its protective gene (IkB-a) maintain endothelial quiescence under normal conditions, but after SARS-Cov-2 binds with ACE2 receptors on the surface of endothelial cells (ECs) and NF-kB activation, the IkB-a genes are insufficient to counteract the action of NF-kB, and ECs become activated. If uncontrolled, ECs progress to apoptosis, necrosis, and endothelial dysfunction. The EC phenotypic changes via the NF-κB pathway result in the release of a variety of molecules/proteins (e.g., IL6, IL8, TNF-related activation protein; E-selectin, P-selectin, ICAM-1, VCAM-1, PECAM-1; D-Dimer, vWF, TF, PAT-1; iNOS, nitrotyrosine; PECAM-1, MadCAM-1, JAM-1, Cav-1; CECs, EMPs; CRP, PTX3). These molecules can directly act on ECs to induce a cytokine storm, inflammation, coagulation, vasodilatation, increased vascular permeability, barrier disturbance, and acute phase response. This endothelial injury can clinically manifest as COVID-19–associated endotheliitis, coagulopathy, and thrombosis. Note that D-dimers are not released from activated ECs and they are one of the fragments produced when plasma cleaves fibrin to break down clots.