PIP2 corrects cerebral blood flow deficits in small vessel disease by rescuing capillary Kir2.1 activity

Abstract

Significance Years before the emergence of infarctions or significant cognitive decline, patients with cerebral small vessel disease (SVD) show a deterioration in the ability of the brain to augment blood flow locally in response to increases in neuronal activity (functional hyperemia). Using a well-characterized genetic mouse model of a hereditary form of SVD, we determined the molecular defect at play in capillary endothelial cells. We found that SVD is associated with reduced synthesis of the phospholipid PIP2, which prevents the Kir2.1 channel-initiated capillary-to-arteriole electrical signaling that supports vasodilatory responses during functional hyperemia. We further show that systemic injection of exogenous PIP2 is sufficient to rescue this deficit in SVD mice, restoring adequate cerebral blood flow in response to neuronal activation. 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.