News-COVID-19: University Of California Study Explains Why COVID-19 Increases Risk Of Strokes

News-COVID-19: A new study by researchers from University Of California-Los Angeles (UCLA) may help explain as to why the risk of strokes is greatly increased in SARS-CoV-2 coronavirus infected individuals. In the last few months of the COVID-19 pandemic, the incidence of strokes has greatly risen and in many countries, excess deaths has been attributed to an increase in strokes. Stroke manifestations have been seen in even those only infected with mild COVID-19 symptoms but also in asymptomatic cases.


 
SARS-CoV-2 infection is associated with an increased rate of cerebrovascular events including ischemic stroke and intracerebral hemorrhage. The mechanisms underlying cerebral endothelial susceptibility and response to SARS-CoV-2 are unknown yet critical to understanding the association of SARS-CoV-2 infection with cerebrovascular events.
 
In this study, endothelial cells were isolated from human brain and analyzed by RNA sequencing. Human umbilical vein and human brain microvascular cells were used in both monolayer culture and endothelialized within a 3-dimensional printed vascular model of the middle cerebral artery. Gene expression levels were measured by quantitative polymerase chain reaction and direct RNA hybridization. Recombinant SARS-CoV-2 S protein and S protein–containing liposomes were used to measure endothelial binding by immunocytochemistry.
 
The study team found that ACE2 (angiotensin-converting enzyme-2) mRNA levels were low in human brain and monolayer endothelial cell culture. Within the 3-dimensional printed vascular model, ACE2 gene expression and protein levels were progressively increased by vessel size and flow rates. SARS-CoV-2 S protein–containing liposomes were detected in human umbilical vein endothelial cells and human brain microvascular endothelial cells in 3-dimensional middle cerebral artery models but not in monolayer culture consistent with flow dependency of ACE2 expression. Binding of SARS-CoV-2 S protein triggered 83 unique genes in human brain endothelial cells including upregulation of complement component C3.
 
The study findings showed that brain endothelial cells are susceptible to direct SARS-CoV-2 infection through flow-dependent expression of ACE2. Viral S protein binding triggers a unique gene expression profile in brain endothelia that may explain the association of SARS-CoV-2 infection with cerebrovascular events.
 
The study findings were published in the peer reviewed journal: Stroke (A Journal of the American Heart Association) https://www.ahajournals.org/doi/10.1161/STROKEAHA.120.032764
 
The study team may help explain how COVID-19 increases the risk for stroke. Scientists made the finding by running fluid spiked with a COVID-19-like protein through a 3D-printed model of the arteries of a patient who had suffered a stroke.
 
Though COVID-19 was first identified by its severe respiratory symptoms, the virus has caused strokes in young people who had no known risk factors. But little is known about how the virus increases the risk for stroke.
 
In order to learn more, the UCLA researchers used a 3D-printed silicone model of blood vessels in the brain to mimic the forces generated by blood pushing through an artery that is abnormally narrowed, a condition called intracranial atherosclerosis.
 
The study team showed that as those forces act on the cells lining the artery, and increases the production of a molecule called angiotensin-converting enzyme 2, or ACE2, which the coronavirus uses to enter cells on the surface of blood vessels.
 
Dr Jason Hinman, an assistant professor of neurology at the David Geffen School of Medicine at UCLA and the study's senior author told Thailand Medical News, "The flow directly influences ACE2 expression."
 
Besides Dr Hinman, the rest of the study's authors include neurologists at the Geffen School of Medicine and scientists from the University California- San Francisco and the Veterans Health Administration.
 
The study team created the model using data from CT scans of blood vessels in a human brain. They then lined the inner surfaces of the models with endothelial cells, the type of cells that line human blood vessels. The models enabled the researchers to mimic the same forces that would act on real blood vessels during a COVID-19 infection.
 
In order to confirm whether coronavirus bobbing along in the bloodstream could latch onto the ACE2 on the endothelial cells in the brain,  the team produced imitation "viruses" ie fatty molecules studded with the spike proteins that coronavirus uses to bind to ACE2.
 
Past research indicated that the coronavirus binds to endothelial cells in other organs, but it was unknown whether that was also happening in the brain.
 
Upon creating the new model, the study team confirmed the particles did indeed interact with the cells lining the blood vessel, mostly in the regions of the brain with higher levels of ACE2.
 
Dr Hinman added, "This finding could explain the increased incidence of strokes seen in COVID-19 infections."
 
Interestingly another significant discovery offered an insight that eventually could help identify people with COVID-19 who may have a higher risk for stroke. When the study team analyzed which genes were turned on in the endothelial cells after the coronavirus spike proteins bound to them, they found that the genes that were activated were a specific set of immune-response genes that are found in brain blood vessel cells, but not in endothelial cells from other organs of the body.
 
Dr Hinman further added, "There's a unique brain endothelial response to the virus that may be helpful in identifying patients who are have a higher risk for stroke."
 
The study team intends to conduct follow-up studies using a live coronavirus in the 3D-printed blood vessel model, which would further confirm the results of the current study and clarify which COVID-19 patients may have a higher risk for stroke.


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