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

Abstract

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.

• Authors: Visesha Kakarla, Naoki Kaneko, May Nour, Kasra Khatibi, Fanny Elahi, David S Liebeskind, Jason D Hinman
• Journal: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism (J Cereb Blood Flow Metab) Vol. 41 Issue 6 Pg. 1179-1192 (06 2021) ISSN: 1559-7016 [Electronic] United States
• PMID: 33530831 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

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

Topics

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