Pathophysiologic mechanisms of cerebral endotheliopathy and stroke due to Sars-CoV-2

J Cereb Blood Flow Metab. 2021 Jun;41(6):1179-1192. doi: 10.1177/0271678X20985666. Epub 2021 Feb 2.


Cerebrovascular events have emerged as a central feature of the clinical syndrome associated with Sars-CoV-2 infection. This increase in infection-related strokes is marked by atypical presentations including stroke in younger patients and a high rate of hemorrhagic transformation after ischemia. A variety of pathogenic mechanisms may underlie this connection. Efforts to identify synergism in the pathophysiology underlying stroke and Sars-CoV-2 infection can inform the understanding of both conditions in novel ways. In this review, the molecular cascades connected to Sars-CoV-2 infection are placed in the context of the cerebral vasculature and in relationship to pathways known to be associated with stroke. Cytokine-mediated promotion of systemic hypercoagulability is suggested while direct Sars-CoV-2 infection of cerebral endothelial cells may also contribute. Endotheliopathy resulting from direct Sars-CoV-2 infection of the cerebral vasculature can modulate ACE2/AT1R/MasR signaling pathways, trigger direct viral activation of the complement cascade, and activate feed-forward cytokine cascades that impact the blood-brain barrier. All of these pathways are already implicated as independent mechanisms driving stroke and cerebrovascular injury irrespective of Sars-CoV-2. Recognizing the overlap of molecular pathways triggered by Sars-CoV-2 infection with those implicated in the pathogenesis of stroke provides an opportunity to identify future therapeutics targeting both Sars-CoV-2 and stroke thereby reducing the impact of the global pandemic.

Keywords: Sars-CoV-2; endothelia; infection; inflammation; stroke.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Angiotensin-Converting Enzyme 2 / metabolism
  • Blood-Brain Barrier / metabolism
  • COVID-19 / complications
  • COVID-19 / pathology*
  • COVID-19 / virology
  • Cerebrovascular Disorders / etiology*
  • Cerebrovascular Disorders / metabolism
  • Complement Activation
  • Humans
  • Proto-Oncogene Mas
  • Renin-Angiotensin System
  • Spike Glycoprotein, Coronavirus / metabolism
  • Stroke / etiology*
  • Stroke / metabolism
  • Virus Internalization


  • Proto-Oncogene Mas
  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2
  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2