Role of Endothelial Cells and Platelets in COVID-Related Cerebrovascular Events

Nabil J. Alkayed, MD, PhD; Marilyn J. Cipolla, PhD

Disclosures

Stroke. 2022;53(7):2389-2392. 

In This Article

Abstract and Introduction

Introduction

In the past 2 years, the world, and health care specifically, has grappled with COVID-19 infections. It is now well established that infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has a vascular component and causes widespread endothelial dysfunction. Endothelial injury with SARS-CoV-2 infection causes pulmonary complications by reducing barrier properties, activating coagulation pathways and increasing the risk of disseminated intravascular coagulation.[1] The attachment of SARS-CoV-2 to ACE2 (angiotensin-converting enzyme type 2) receptors on endothelial cells, in the presence of TMPRSS2 (transmembrane protease serine 2), allows viral entry via clathrin-mediated endocytosis (Figure [A]) that activates a cascade of events causing endothelial injury and increased clot formation.[2] In addition to direct endothelial injury, SARS-CoV-2 binding to ACE2 decreases local beneficial effects of ACE2 on inhibition of the kallikrein-bradykinin system that further drives coagulation and inflammation (Figure [B] and [C]).[3] Given these known effects of SARS-CoV-2 infection on the vasculature, it is not surprising that SARS-CoV-2 also increases the rate of ischemic stroke and intracerebral hemorrhage, most notably in the young.[4,5] In addition, SARS-CoV-2 infection seems to disproportionally increase cryptogenic stroke and mortality suggesting the association between COVID-19 and stroke may be atypical with varying degrees of susceptibility.[6] Understanding the unique effects of SARS-CoV-2 infection on the cerebral endothelium is important for preventing and treating stroke in COVID-19 patients. In a novel study by Kaneko et al,[7] human endothelial cells and a 3-dimensional printed endothelialized model system were used to investigate ACE2 expression and underlying factors that affect cerebrovascular susceptibility to SARS-CoV-2 infection. In freshly obtained human brain and endothelium, mRNA levels of both ACE2 and TMPRSS2 were below detection. However, another ACE2 cofactor furin was found instead, suggesting protease-dependent membrane fusion (Figure [B]) as a means for SARS-CoV-2 entry into brain endothelium. Interestingly, when monolayers of human umbilical vein endothelial cells or human brain microvascular endothelial cells were subjected to high or low shear stress in the 3-dimensional model system, ACE2 expression increased substantially.[7] Further, when endothelial cells were grown in a 3D model that mimicked stenosis, ACE2 levels significantly increased compared with the nonstenotic area.[7] These findings may help explain localized endothelial injury and thrombosis with SARS-CoV-2 infection that leads to stroke—especially in young patients without typical stroke risk factors—but also why patients with co-morbidities that have preexisting vascular dysfunction such as diabetes and hypertension fair worse with COVID-19 infection.[8] Activation of the inflammatory cascade ("cytokine storm") that exacerbates endothelial dysfunction and blood-brain barrier permeability represents another means by which SARS-CoV-2 adversely impacts the cerebrovasculature that may be involved in COVID-19 stroke pathophysiology.[9]

Figure.

Mechanisms of severe acute respiratory syndrome coronavirus-2 (SAR-CoV2) entry and increased risk of stroke. A, ACE2 (receptor-mediated endocytosis in endothelial cells and cathepsin L-dependent activation. B, Protease (TMPRSS2 [transmembrane protease serine 2] and furin)-mediated membrane fusion and viral activation. C, Viral infection activates endothelial and immune cells, which secrete cytokines and chemokines that contribute to the cytokine storm and create a vicious loop that exacerbates endothelial cell activation and systemic inflammation, and lead to platelet activation and platelet-immune cell aggregation. Activated platelets and immune cells further contribute to the thromboinflammatory state by secreting cytokines, activating coagulation and through the formation of neutrophil extracellular traps. This is further exacerbated by complement activation. Platelet activation is amplified by ADP acting on the purinergic receptor P2Y12 and thromboxane A2 (TxA2) acting on the thromboxane-prostanoid (TP) receptor. Activated endothelium expresses cell adhesion molecules (CAMs) and both endothelium and immune cells express tissue factor (TF), which activates coagulation, leading to thrombosis that further exacerbates endothelial injury and dysfunction, and heightens the risk of stroke.

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