Astrocytic Slc4a4 regulates blood-brain barrier integrity in healthy and stroke brains via a NO-CCL2-CCR2 pathway

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Abstract

Astrocytes play vital roles in blood-brain barrier (BBB) maintenance, yet how they support BBB integrity under normal or pathological conditions remains poorly defined. Recent evidence suggests pH homeostasis is a new cellular mechanism important for BBB integrity. In the current study, we investigated the function of an astrocyte-specific pH regulator, Slc4a4, in BBB maintenance and repair. We show that astrocytic Slc4a4 is required for normal astrocyte morphological complexity and BBB function. Multi-omics analyses identified increased astrocytic secretion of CCL2 coupled with dysregulated arginine-NO metabolism after Slc4a4 deletion. Using a model of ischemic stroke, we found that loss of Slc4a4 exacerbates BBB disruption and reactive gliosis, which were both rescued by pharmacological or genetic inhibition of the NO-CCL2 pathway in vivo. Together, our study identifies the astrocytic Slc4a4-NO-CCL2 axis as a pivotal mechanism controlling BBB integrity and repair, while providing insights for a novel therapeutic approach against BBB-related CNS disorders.

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Most cited references 72

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Astrocyte-endothelial interactions at the blood-brain barrier.

N. Abbott, Lars Rönnbäck, Elisabeth Hansson (2006)

The blood-brain barrier, which is formed by the endothelial cells that line cerebral microvessels, has an important role in maintaining a precisely regulated microenvironment for reliable neuronal signalling. At present, there is great interest in the association of brain microvessels, astrocytes and neurons to form functional 'neurovascular units', and recent studies have highlighted the importance of brain endothelial cells in this modular organization. Here, we explore specific interactions between the brain endothelium, astrocytes and neurons that may regulate blood-brain barrier function. An understanding of how these interactions are disturbed in pathological conditions could lead to the development of new protective and restorative therapies.

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Stroke.

Graeme Hankey (2017)

In the past decade, the definition of stroke has been revised and major advances have been made for its treatment and prevention. For acute ischaemic stroke, the addition of endovascular thrombectomy of proximal large artery occlusion to intravenous alteplase increases functional independence for a further fifth of patients. The benefits of aspirin in preventing early recurrent ischaemic stroke are greater than previously recognised. Other strategies to prevent recurrent stroke now include direct oral anticoagulants as an alternative to warfarin for atrial fibrillation, and carotid stenting as an alternative to endarterectomy for symptomatic carotid stenosis. For acute intracerebral haemorrhage, trials are ongoing to assess the effectiveness of acute blood pressure lowering, haemostatic therapy, minimally invasive surgery, anti-inflammation therapy, and neuroprotection methods. Pharmacological and stem-cell therapies promise to facilitate brain regeneration, rehabilitation, and functional recovery. Despite declining stroke mortality rates, the global burden of stroke is increasing. A more comprehensive approach to primary prevention of stroke is required that targets people at all levels of risk and is integrated with prevention strategies for other diseases that share common risk factors.

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Glial regulation of the cerebral microvasculature.

Costantino Iadecola, Maiken Nedergaard (2007)

The brain is a heterogeneous organ with regionally varied and constantly changing energetic needs. Blood vessels in the brain are equipped with control mechanisms that match oxygen and glucose delivery through blood flow with the local metabolic demands that are imposed by neural activity. However, the cellular bases of this mechanism have remained elusive. A major advance has been the demonstration that astrocytes, cells with extensive contacts with both synapses and cerebral blood vessels, participate in the increases in flow evoked by synaptic activity. Their organization in nonoverlapping spatial domains indicates that they are uniquely positioned to shape the spatial distribution of the vascular responses that are evoked by neural activity. Astrocytic calcium is an important determinant of microvascular function and may regulate flow independently of synaptic activity. The involvement of astrocytes in neurovascular coupling has broad implications for the interpretation of functional imaging signals and for the understanding of brain diseases that are associated with neurovascular dysfunction.

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Author and article information

Journal

Journal ID (nlm-ta): bioRxiv

Journal ID (publisher-id): BIORXIV

Title: bioRxiv

Publisher: Cold Spring Harbor Laboratory

Publication date (Electronic): 03 April 2023

Electronic Location Identifier: 2023.04.03.535167

Affiliations

[1 ]Department of Pediatrics, Section of Neurology, Baylor College of Medicine, Houston, TX, USA

[2 ]Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX, USA

[3 ]Cancer and Cell Biology Program, Baylor College of Medicine, Houston, TX, USA

[4 ]Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, CO, USA.

[5 ]Physics Department, University of Rhode Island, Kingston, RI, USA

[6 ]Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, USA

[7 ]Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, Houston, TX, USA

[8 ]Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA

[9 ]Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA

Author notes

Author contribution

Q.Y and H.K.L conceived the project and design the experiments; Q.Y, J.J, C.W, H.O, T.J.C performed the experiments; Y.K.R, A.D.A, S.Y.J, C.Z, H.K.L provided reagent; S.P.M provided expertise. Q.Y, T.J.C and H.K.L wrote and edit the manuscript.

[* ]Correspondence: hyunkyol@ 123456bcm.edu

Article

DOI: 10.1101/2023.04.03.535167

PMC ID: 10103986

PubMed ID: 37066295

SO-VID: 68071c1d-4e0b-4c76-9a3b-42bdc48c0c22

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This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.

Astrocytic Slc4a4 regulates blood-brain barrier integrity in healthy and stroke brains via a NO-CCL2-CCR2 pathway

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Abstract

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Nanoparticles to cross the blood-brain barrier (BBB)

Most cited references 72

Astrocyte-endothelial interactions at the blood-brain barrier.

Stroke.

Glial regulation of the cerebral microvasculature.

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