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

Hirunpattarasilp et al. show that the binding of SARS-CoV-2 inactivates ACE2 on capillary pericytes, leading to pericyte contraction, capillary constriction and a reduction of blood flow in the brain (and possibly the kidney and heart). A commonly used drug, losartan, can prevent these effects. The SARS-CoV-2 receptor, ACE2, is found on pericytes, contractile cells enwrapping capillaries that regulate brain, heart and kidney blood flow. ACE2 converts vasoconstricting angiotensin II into vasodilating angiotensin-(1-7). In brain slices from hamster, which has an ACE2 sequence similar to human ACE2, angiotensin II evoked a small pericyte-mediated capillary constriction via AT1 receptors, but evoked a large constriction when the SARS-CoV-2 receptor binding domain (RBD, original Wuhan variant) was present. A mutated non-binding RBD did not potentiate constriction. A similar RBD-potentiated capillary constriction occurred in human cortical slices, and was evoked in hamster brain slices by pseudotyped virions expressing SARS-CoV-2 spike protein. This constriction reflects an RBD-induced decrease in the conversion of angiotensin II to angiotensin-(1-7) mediated by removal of ACE2 from the cell surface membrane and was mimicked by blocking ACE2. The clinically used drug losartan inhibited the RBD-potentiated constriction. Thus, AT1 receptor blockers could be protective in COVID-19 by preventing pericyte-mediated blood flow reductions in the brain, and perhaps the heart and kidney.

Automated summary

The binding of SARS-CoV-2 to ACE2 on capillary pericytes causes pericyte contraction and capillary constriction, leading to reduced blood flow in the brain, heart, and kidney. The drug losartan can prevent these effects.