PIP <sub>2</sub> corrects cerebral blood flow deficits in small vessel disease by rescuing capillary Kir2.1 activity
Fabrice Dabertrand, Osama F. Harraz, Masayo Koide, Thomas A. Longden, Amanda C. Rosehart, David C. Hill‐Eubanks, Anne Joutel, Mark T. Nelson
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 PIP 2 , 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 PIP 2 is sufficient to rescue this deficit in SVD mice, restoring adequate cerebral blood flow in response to neuronal activation.