PIP2 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

doi:10.1073/pnas.2025998118

PIP₂ corrects cerebral blood flow deficits in small vessel disease by rescuing capillary Kir2.1 activity

Proc Natl Acad Sci U S A. 2021 Apr 27;118(17):e2025998118. doi: 10.1073/pnas.2025998118.

Authors

Fabrice Dabertrand^{1

2

3}, Osama F Harraz^{4

5}, Masayo Koide^{4

5}, Thomas A Longden⁴, Amanda C Rosehart^{4

2}, David C Hill-Eubanks⁴, Anne Joutel^{4

6

7}, Mark T Nelson^{1

5

8}

Affiliations

¹ Department of Pharmacology, Larner College of Medicine, University of Vermont, Burlington, VT 05405; fabrice.dabertrand@cuanschutz.edu Mark.Nelson@uvm.edu.
² Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045.
³ Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045.
⁴ Department of Pharmacology, Larner College of Medicine, University of Vermont, Burlington, VT 05405.
⁵ Vermont Center for Cardiovascular and Brain Health, University of Vermont, Burlington, VT 05405.
⁶ Institute of Psychiatry and Neurosciences of Paris, INSERM UMR1266, University of Paris, F-75014 Paris, France.
⁷ Psychiatrie et Neurosciences, Groupe Hospitalier Universitaire Paris, F-75014 Paris, France.
⁸ Division of Cardiovascular Sciences, University of Manchester, Manchester M13 9PL, United Kingdom.

Abstract

Cerebral small vessel diseases (SVDs) are a central link between stroke and dementia-two comorbidities without specific treatments. Despite the emerging consensus that SVDs are initiated in the endothelium, the early mechanisms remain largely unknown. Deficits in on-demand delivery of blood to active brain regions (functional hyperemia) are early manifestations of the underlying pathogenesis. The capillary endothelial cell strong inward-rectifier K⁺ channel Kir2.1, which senses neuronal activity and initiates a propagating electrical signal that dilates upstream arterioles, is a cornerstone of functional hyperemia. Here, using a genetic SVD mouse model, we show that impaired functional hyperemia is caused by diminished Kir2.1 channel activity. We link Kir2.1 deactivation to depletion of phosphatidylinositol 4,5-bisphosphate (PIP₂), a membrane phospholipid essential for Kir2.1 activity. Systemic injection of soluble PIP₂ rapidly restored functional hyperemia in SVD mice, suggesting a possible strategy for rescuing functional hyperemia in brain disorders in which blood flow is disturbed.

Keywords: CADASIL; PIP2; cerebral small vessel diseases; functional hyperemia; potassium channel.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Video-Audio Media

MeSH terms

Animals
Cerebral Small Vessel Diseases / etiology*
Cerebral Small Vessel Diseases / metabolism
Cerebrovascular Circulation*
Disease Models, Animal
Endothelial Cells / metabolism
Hyperemia / etiology*
Hyperemia / metabolism
Male
Mice, Transgenic
Phosphatidylinositol 4,5-Diphosphate / metabolism*
Potassium Channels, Inwardly Rectifying / metabolism*

Substances

Kir2.1 channel
Phosphatidylinositol 4,5-Diphosphate
Potassium Channels, Inwardly Rectifying

Abstract

Publication types

MeSH terms

Substances

Grants and funding