SARS-CoV-2 triggers pericyte-mediated cerebral capillary constriction

Area of Science:

• Cardiovascular Biology
• Neuroscience
• Virology

Background:

• Angiotensin-converting enzyme 2 (ACE2) regulates blood flow by converting angiotensin II to angiotensin-(1-7).
• ACE2 is present on pericytes, cells crucial for regulating blood flow in the brain, heart, and kidneys.
• SARS-CoV-2 utilizes ACE2 as its receptor.

Purpose of the Study:

• To investigate the effect of the SARS-CoV-2 receptor binding domain (RBD) on pericyte-mediated capillary constriction.
• To determine the mechanism behind RBD-induced capillary constriction and its potential therapeutic implications.

Main Methods:

• Experiments were conducted using hamster and human brain slices.
• The study utilized angiotensin II, SARS-CoV-2 RBD (Wuhan variant), mutated RBD, and pseudotyped virions expressing SARS-CoV-2 spike protein.
• Capillary constriction was measured, and the role of ACE2 activity and AT1 receptors was assessed.
• The effect of losartan, an AT1 receptor blocker, was evaluated.

Main Results:

• The SARS-CoV-2 RBD significantly potentiated angiotensin II-induced capillary constriction in hamster and human brain slices.
• This potentiation was dependent on RBD binding and was not observed with a mutated non-binding RBD.
• The constriction mechanism involved an RBD-induced decrease in ACE2 activity, leading to reduced angiotensin-(1-7) production and removal of ACE2 from the cell surface.
• Losartan effectively inhibited the RBD-potentiated capillary constriction.

Conclusions:

• The SARS-CoV-2 RBD can induce pericyte-mediated capillary constriction, potentially impairing blood flow in the brain, heart, and kidneys.
• AT1 receptor blockers, like losartan, may offer protective benefits against COVID-19 by preventing these blood flow reductions.