Dabertrand et al. Proc Natl Acad Sci U S A. 2021


 

PIP2 corrects cerebral blood flow deficits in small vessel disease by rescuing capillary Kir2.1 activity.  Dabertrand F, Harraz OF, Koide M, Longden TA, Rosehart AC, Hill-Eubanks DC, Joutel A, Nelson MT. Proc Natl Acad Sci U S A. 2021 Apr 27;118(17). doi: 10.1073/pnas.2025998118. PubMed PMID: 33875602.

 

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.

 

Keywords: CADASIL; PIP2; cerebral small vessel diseases; functional hyperemia; potassium channel.

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