Endothelial Dysfunction in the Brain

Abstract

The Coronavirus disease 2019 (COVID)-19 pandemic has already affected millions worldwide, with a current mortality rate of 2.2%. While it is well-established that severe acute respiratory syndrome-coronavirus-2 causes upper and lower respiratory tract infections, a number of neurological sequelae have now been reported in a large proportion of cases. Additionally, the disease causes arterial and venous thromboses including pulmonary embolism, myocardial infarction, and a significant number of cerebrovascular complications. The increasing incidence of large vessel ischemic strokes as well as intracranial hemorrhages, frequently in younger individuals, and associated with increased morbidity and mortality, has raised questions as to why the brain is a major target of the disease. COVID-19 is characterized by hypercoagulability with alterations in hemostatic markers including high D-dimer levels, which are a prognosticator of poor outcome. Together with findings of fibrin-rich microthrombi, widespread extracellular fibrin deposition in affected various organs and hypercytokinemia, this suggests that COVID-19 is more than a pulmonary viral infection. Evidently, COVID-19 is a thrombo-inflammatory disease. Endothelial cells that constitute the lining of blood vessels are the primary targets of a thrombo-inflammatory response, and severe acute respiratory syndrome coronavirus 2 also directly infects endothelial cells through the ACE2 (angiotensin-converting enzyme 2) receptor. Being highly heterogeneous in their structure and function, differences in the endothelial cells may govern the susceptibility of organs to COVID-19. Here, we have explored how the unique characteristics of the cerebral endothelium may be the underlying reason for the increased rates of cerebrovascular pathology associated with COVID-19.

Ceramide Metabolism and Parkinson’s Disease—Therapeutic Targets

“…Vascular dysfunction has been associated with the risk of neurodegeneration [107]. Notably, cerebral ischemia has been linked to pro-inflammatory processes in endothelial cells and loss of the integrity of the blood-brain barrier [108,109].…”

Imaging features and ultraearly hematoma growth in intracerebral hemorrhage associated with COVID-19

“…Several other mechanisms may explain our observations. Endothelial injury is a key event in the natural history of COVID-19 infection and the presence of multifocal endothelial damage to cerebral small vessels may explain the presence of multiple sites of bleeding and the faster bleeding pace in COV19 + patients [ 10 ]. Impaired hemostasis may also account for our findings, arising from severe systemic inflammation with massive cytokine release [ 11 ].…”

The Immunopathogenesis of Neuroinvasive Lesions of SARS-CoV-2 Infection in COVID-19 Patients

“…ACE2 usage by the virus and receptor shedding reduced cell surface expression of ACE2 and endothelial dysfunction. Dysregulation of ACE2 enzymatic function may also lead to dysregulation of the brain renin-angiotensin system (B-RAS) whilst overexpression of Ang II and dysregulated blood pressure can impact on brain endothelial cell dysfunction (119). High levels of Ang II can also trigger an increase in proinflammatory cytokine levels and promote a cytokine storm within the brain (120).…”