PIP2 corrects cerebral blood flow deficits in small vessel disease by rescuing capillary Kir2.1 activity
Proceedings of the National Academy of Sciences, 2021•National Acad Sciences
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 …
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 …
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.
National Acad Sciences