PI3K block restores age-dependent neurovascular coupling defects associated with cerebral small vessel disease

Neurovascular coupling (NVC), a vital physiological process that rapidly
and precisely directs localized blood flow to the most active regions of
the brain, is accomplished in part by the vast network of cerebral
capillaries acting as a sensory web capable of detecting increases in
neuronal activity and orchestrating the dilation of upstream parenchymal
arterioles. Here, we report a Col4a1 mutant mouse model of cerebral small
vessel disease (cSVD) with age-dependent defects in capillary-to-arteriole
dilation, functional hyperemia in the brain, and memory. The fundamental
defect in aged mutant animals was the depletion of the minor membrane
phospholipid phosphatidylinositol 4,5 bisphosphate (PIP2) in brain
capillary endothelial cells, leading to the loss of inwardly rectifier K+
(Kir2.1) channel activity. Blocking phosphatidylinositol-3-kinase (PI3K),
an enzyme that diminishes the bioavailability of PIP2 by converting it to
phosphatidylinositol (3,4,5)-trisphosphate (PIP3), restored Kir2.1 channel
activity, capillary-to-arteriole dilation, and functional hyperemia. In
longitudinal studies, chronic PI3K inhibition also improved the memory
function of aged Col4a1 mutant mice. Our data suggest that PI3K inhibition
is a viable therapeutic strategy for treating defective NVC and cognitive
impairment associated with cSVD.