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

Abstract

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 (PIP 2 ) in brain capillary endothelial cells, leading to the loss of inwardly rectifying K + (Kir2.1) channel activity. Blocking phosphatidylinositol-3-kinase (PI3K), an enzyme that diminishes the bioavailability of PIP 2 by converting it to phosphatidylinositol (3, 4, 5)-trisphosphate (PIP 3 ), 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.

Pathophysiology of cerebral small vessel disease: a journey through recent discoveries

“…Strikingly, Col4a1 -mutant and CADASIL mice, like hypertensive mice, exhibit an age-dependent reduction in functional hyperemia that also results from defective capillary-to-arteriole signaling as a consequence of diminished capillary endothelial cell Kir2.1 channel activity. Remarkably, the fundamental defect underlying this channelopathy (depletion of the minor membrane phospholipid phosphatidylinositol 4,5-bisphosphate (PIP 2 ), a key activator of the Kir2.1 channel) is similar in Col4a1 -mutant and CADASIL mice, although the intrinsic mechanisms differ ( 25 , 88 , 92 , 93 , 109 – 111 ). Interestingly, restoring functional hyperemia by depleting PVMs in hypertensive mice and by chronic inhibition of phosphoinositide-3-kinase (PI3K) in Col4a1 -mutant mice improved memory deficits ( 106 , 111 ).…”

“…Remarkably, the fundamental defect underlying this channelopathy (depletion of the minor membrane phospholipid phosphatidylinositol 4,5-bisphosphate (PIP 2 ), a key activator of the Kir2.1 channel) is similar in Col4a1 -mutant and CADASIL mice, although the intrinsic mechanisms differ ( 25 , 88 , 92 , 93 , 109 – 111 ). Interestingly, restoring functional hyperemia by depleting PVMs in hypertensive mice and by chronic inhibition of phosphoinositide-3-kinase (PI3K) in Col4a1 -mutant mice improved memory deficits ( 106 , 111 ). Although these findings support the hypothesis that a chronic reduction in NVC could account for cognitive deficits, further studies are needed to substantiate this relationship and rule out possible confounding effects of specific experimental maneuvers, which may have additional effects on the brain or brain vessels.…”