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.
Funder
American Heart Association
Fondation Leducq
HHS | NIH | National Institute of General Medical Sciences
HHS | NIH | National Institute of Neurological Disorders and Stroke
European Union Horizon 2020 Research and Innovation Program SVDs@target
French National Agency of Research
HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases
HHS | NIH | National Heart, Lung, and Blood Institute
Publisher
Proceedings of the National Academy of Sciences
Cited by
42 articles.
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