PIP2 corrects cerebral blood flow deficits in small vessel disease by rescuing capillary Kir2.1 activity.
Proc Natl Acad Sci U S A
; 118(17)2021 04 27.
Article
em En
| MEDLINE
| ID: mdl-33875602
ABSTRACT
Cerebral small vessel diseases (SVDs) are a central link between stroke and dementia-two comorbidities without specific treatments. Despite the emerging consensus that SVDs are initiated in the endothelium, the early mechanisms remain largely unknown. Deficits in on-demand delivery of blood to active brain regions (functional hyperemia) are early manifestations of the underlying pathogenesis. The capillary endothelial cell strong inward-rectifier K+ channel Kir2.1, which senses neuronal activity and initiates a propagating electrical signal that dilates upstream arterioles, is a cornerstone of functional hyperemia. Here, using a genetic SVD mouse model, we show that impaired functional hyperemia is caused by diminished Kir2.1 channel activity. We link Kir2.1 deactivation to depletion of phosphatidylinositol 4,5-bisphosphate (PIP2), a membrane phospholipid essential for Kir2.1 activity. Systemic injection of soluble PIP2 rapidly restored functional hyperemia in SVD mice, suggesting a possible strategy for rescuing functional hyperemia in brain disorders in which blood flow is disturbed.
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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Circulação Cerebrovascular
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Fosfatidilinositol 4,5-Difosfato
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Canais de Potássio Corretores do Fluxo de Internalização
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Doenças de Pequenos Vasos Cerebrais
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Hiperemia
Limite:
Animals
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article