Edited by Fabrice Dabertrand, University of Colorado Anschutz Medical Campus, Aurora, CO; received April 20, 2023; accepted July 17, 2023 by Editorial Board Member Mark T. Nelson
August 22, 2023
120 (35) e2306479120
Significance
Cerebral small vessel diseases (cSVDs), a group of familial and idiopathic pathologies, are a leading cause of vascular contributions to cognitive impairment and dementia. The underlying mechanisms are poorly understood and there are no specific treatment options available. Here, we utilized a mouse model of cSVD caused by a mutation in the gene encoding collagen type IV alpha1 (COL4A1) to understand the pathogenesis of the disease. We found that middle-aged mutant mice had impaired neurovascular coupling, functional hyperemia, and memory function. These deficits were caused by impaired activity of the inwardly rectifying K+ (Kir2.1) channel. Kir2.1 activity, functional hyperemia, and memory function were restored by chronic phosphatidylinositol-3-kinase (PI3K) inhibition, identifying a therapeutic target for cSVDs.
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.
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Data, Materials, and Software Availability
Acknowledgments
This study was supported by grants from the NIH (NHLBI R35155008 and NIGMS P20GM130459 to S.E.; NINDS R01NS096173 to D.B.G.; and NINDS RF1NS110044 and R33NS115132 to S.E. and D.B.G.) and the American Heart Association (Career Development Award 23CDA1054627 to P.T). The Transgenic Genotyping and Phenotyping Core and the High Spatial and Temporal Resolution Imaging Core at the COBRE Center for Molecular and Cellular Signaling in the Cardiovascular System, University of Nevada, Reno are maintained by grants from NIH/NIGMS (P20GM130459 Sub#5451 and P20GM130459 Sub#5452). The University of California, San Francisco Department of Ophthalmology is supported by a Vision Core grant NEI P30EY002162 and an unrestricted grant from Research to Prevent Blindness, New York, NY.
Author contributions
P.T., E.Y., S.A., and S.E. designed research; P.T., E.Y., S.A., A.S.S., X.G., and M.M.C. performed research; C.L.-D. and D.B.G. contributed new reagents/analytic tools; P.T., E.Y., S.A., A.S.S., and S.E. analyzed data; and P.T. and S.E. wrote the paper.
Competing interests
S.E. and D.B.G. have filed a provisional patent for the use of PI3 kinase inhibitors to treat cSVDs.
Supporting Information
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Information & Authors
Information
Published in
Proceedings of the National Academy of Sciences
Vol. 120 | No. 35
August 29, 2023
Classifications
Copyright
Data, Materials, and Software Availability
Submission history
Received: April 20, 2023
Accepted: July 17, 2023
Published online: August 22, 2023
Published in issue: August 29, 2023
Keywords
- COL4A1
- extracellular matrix
- cerebral small vessel disease
- functional hyperemia
- Kir2.1 channels
Acknowledgments
This study was supported by grants from the NIH (NHLBI R35155008 and NIGMS P20GM130459 to S.E.; NINDS R01NS096173 to D.B.G.; and NINDS RF1NS110044 and R33NS115132 to S.E. and D.B.G.) and the American Heart Association (Career Development Award 23CDA1054627 to P.T). The Transgenic Genotyping and Phenotyping Core and the High Spatial and Temporal Resolution Imaging Core at the COBRE Center for Molecular and Cellular Signaling in the Cardiovascular System, University of Nevada, Reno are maintained by grants from NIH/NIGMS (P20GM130459 Sub#5451 and P20GM130459 Sub#5452). The University of California, San Francisco Department of Ophthalmology is supported by a Vision Core grant NEI P30EY002162 and an unrestricted grant from Research to Prevent Blindness, New York, NY.
Author Contributions
P.T., E.Y., S.A., and S.E. designed research; P.T., E.Y., S.A., A.S.S., X.G., and M.M.C. performed research; C.L.-D. and D.B.G. contributed new reagents/analytic tools; P.T., E.Y., S.A., A.S.S., and S.E. analyzed data; and P.T. and S.E. wrote the paper.
Competing Interests
S.E. and D.B.G. have filed a provisional patent for the use of PI3 kinase inhibitors to treat cSVDs.
Notes
This article is a PNAS Direct Submission. F.D. is a guest editor invited by the Editorial Board.
Authors
Affiliations
Department of Pharmacology, Center for Molecular and Cellular Signaling in the Cardiovascular System University of Nevada, Reno School of Medicine, Reno, NV 89557-0318
Department of Pharmacology, Center for Molecular and Cellular Signaling in the Cardiovascular System University of Nevada, Reno School of Medicine, Reno, NV 89557-0318
Department of Pharmacology, Center for Molecular and Cellular Signaling in the Cardiovascular System University of Nevada, Reno School of Medicine, Reno, NV 89557-0318
Department of Pharmacology, Center for Molecular and Cellular Signaling in the Cardiovascular System University of Nevada, Reno School of Medicine, Reno, NV 89557-0318
Department of Ophthalmology and Anatomy, Institute for Human Genetics, University of California San Francisco School of Medicine, San Francisco, CA 94143
Xiao Gao
Department of Physical Therapy and Rehabilitation Science, University of California, San Francisco, CA 94158
Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA 94143-0628
Department of Physical Therapy and Rehabilitation Science, University of California, San Francisco, CA 94158
Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA 94143-0628
Department of Ophthalmology and Anatomy, Institute for Human Genetics, University of California San Francisco School of Medicine, San Francisco, CA 94143
Department of Pharmacology, Center for Molecular and Cellular Signaling in the Cardiovascular System University of Nevada, Reno School of Medicine, Reno, NV 89557-0318
Notes
1
P.T., E.Y., and S.A. contributed equally to this work.
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