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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 (PIP₂) 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 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.

SUBMITTER: Thakore P

PROVIDER: S-EPMC10467353 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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

Thakore Pratish P Yamasaki Evan E Ali Sher S Sanchez Solano Alfredo A Labelle-Dumais Cassandre C Gao Xiao X Chaumeil Myriam M MM Gould Douglas B DB Earley Scott S

Proceedings of the National Academy of Sciences of the United States of America 20230822 35

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 <i>Col4a1</i> mutant mouse model of cerebral small vessel disease (cSVD) with age-dependent defects in capillary-t ...[more]

PMID: 37607233

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Project description:PurposeThe pathogenesis of cerebral small vessel disease (cSVD) remains elusive despite evidence of an association between white matter hyperintensities (WMH) and endothelial cerebrovascular dysfunction. Neurovascular coupling (NVC) may be a practical alternative measure of endothelial function. We performed a systematic review of reported associations between NVC and cSVD.MethodsEMBASE and PubMed were searched for studies reporting an association between any STRIVE-defined marker of cSVD and a measure of NVC during functional magnetic resonance imaging, transcranial Doppler, positron emission tomography, near-infrared spectroscopy or single-photon emission computed tomography, from inception to November 3rd, 2022. Where quantitative data was available from studies using consistent tests and analyses, results were combined by inverse-variance weighted random effects meta-analysis.FindingsOf 29 studies (19 case-controls; 10 cohorts), 26 reported decreased NVC with increasing severity of cSVD, of which 18 were individually significant. In 28 studies reporting associations with increasing WMH, 25 reported reduced NVC. Other markers of cSVD were associated with reduced NVC in: eight of nine studies with cerebral microbleeds (six showing a significant effect); three of five studies with lacunar stroke; no studies reported an association with enlarged perivascular spaces. Specific SVD diseases were particularly associated with reduced NVC, including six out of seven studies in cerebral amyloid angiopathy and all four studies in CADASIL. In limited meta-analyses, %BOLD occipital change to a visual stimulus was consistently reduced with more severe WMH (seven studies, SMD -1.51, p < 0.01) and increasing microbleeds (seven studies, SMD -1.31, p < 0.01).Discussion and conclusionIn multiple, small studies, neurovascular coupling was reduced in patients with increasing severity of all markers of cSVD in sporadic disease, CAA and CADASIL. Cerebrovascular endothelial dysfunction, manifest as impaired NVC, may be a common marker of physiological dysfunction due to small vessel injury that can be easily measured in large studies and clinical practice.

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

Publications

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

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