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

Abstract

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.

A Brief Overview of Neutrophils in Neurological Diseases

“…It is reported that SARS-CoV-2 can enter the central nervous system via dysregulation of the BBB [75,76]. Once inside the brain, it can constrict the capillaries and reduce the blood flow via binding ACE2 on the pericytes [77]. SARS-CoV-2 also increases the viscosity of the blood, which causes the reduced blood flow in the cerebral capillaries [78].…”

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“…Pericytes are also involved: Bocci et al demonstrated that pericytes have the ACE2 receptor and that cells of cerebral capillaries from a SARS-CoV-2 infected patient showed viral RNA, which is a possible source of entry into the brain by SARS-CoV-2 [ 43 ]. Hirunpattarasilp et al induced capillary constriction by exposing human cortical slices to SARS-CoV-2 spike protein, resulting in decreased conversion of vasoconstricting angiotensin II to vasodilating angiotensin I; that was shown as caused by the occupation of ACE2 by SARS-CoV-2 because the effect from blocking angiotensin1 mimicked the effect from blocking ACE2 [ 44 ].…”

What Are the Roles of Pericytes in the Neurovascular Unit and Its Disorders?

“…60 Pericytes also respond to vasoactive substances such as norepinephrine 61 and angiotensin II. 62 They express angiotensin-converting enzyme 2 (ACE2), which converts vasoconstricting angiotensin II into vasodilating angiotensin-(1-7). 62 The proportion of microvascular pericytes that are able to contract varies depending on the tissue, species, developmental stage, and localization along the arteriovenous length.…”

“…62 They express angiotensin-converting enzyme 2 (ACE2), which converts vasoconstricting angiotensin II into vasodilating angiotensin-(1-7). 62 The proportion of microvascular pericytes that are able to contract varies depending on the tissue, species, developmental stage, and localization along the arteriovenous length. 63 In response to microenvironmental changes, pericytes may also secrete different molecules that function as paracrine signals.…”

“…115 Pericytes may also be involved in the vascular complications of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. 116 SARS-CoV-2 binding removes ACE2 from the cell surface membrane and thus impairs conversion of angiotensin II to angiotensin-(1-7) 62 leading pericyte-mediated angiotensin II evoked cerebral capillary constriction. 116…”