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Signaling at the Gliovascular Interface
Open accessAbstract
Advances in fluorescent calcium indicating dyes over the past decade have identified calcium signaling as the tool by which astrocytes communicate among themselves and with neighboring neurons. Studies of astrocyte-neuron interactions have shown that calcium signaling is a potent modulator of the strength of both excitatory and inhibitory synapses. The concept that astrocytes possess a mechanism for rapid cell communication has not been incorporated, however, into the supportive functions of astrocytes. Because many of the classical tasks of astrocytes are linked to the blood-brain barrier, we have here examined the expression of proteins required for calcium signaling in their vascular end-foot processes. The gap junction protein, Cx43, was expressed intensively around the vessels interconnecting astrocytic end-foot processes. These gap junctions permitted diffusion of Lucifer yellow, specifically along the path of glial end feet apposed to the vessel wall. The purinergic receptors, P2Y(2) and P2Y(4), were also strongly expressed at the gliovascular interface and colocalized with GFAP around larger vessels in cortex. Multiphoton imaging of freshly prepared brain slices loaded with Fluo-4/AM revealed that ATP mobilized cytosolic calcium in astrocytic end feet, whereas electrical stimulation triggered calcium waves propagating along the vessel wall. Brain endothelial cells and pericytes were physically separated from astrocytes by the basal lamina and responded only weakly to ATP. These observations identify astrocytic end-foot processes plastered at the vessel wall as a center for purinergic signaling. It is speculated that calcium signaling may play a role in astrocytic functions related to the blood-brain barrier, including blood flow regulation, metabolic trafficking, and water homeostasis.
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“Yet brain tissue itself lacks histologically-distinct lymphatic vessels. Rather, fluid clearance from the brain proceeds via the glymphatics, a structurally distinct system of fluid transport that utilizes the perivascular spaces created by the vascular endfeet of astrocytes (26).”
From Glymphatic failure as a final common pathway to dementia (2020) · cites this paper as [26]
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Metadata
- Authors
- Simard, M., Arcuino, G., Takano, T., Liu, Q. S., & Nedergaard, M.
- Affiliations
- New York Medical College (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2003-10-08
- Volume
- 23
- Issue
- 27
- Pages
- 9254-9262
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6740832
- OpenAlex
- W2105112166
- Cited by
- 586
- References
- 55
- Citations by year
- 2026: 6 · 2025: 16 · 2024: 17 · 2023: 19 · 2022: 14 · 2021: 24 · 2020: 20 · 2019: 18 · 2018: 16 · 2017: 30 · 2016: 26 · 2015: 45 · 2014: 26 · 2013: 36 · 2012: 41
- FWCI
- 17.36
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (7k08ns001672-06)
- National Institute of Neurological Disorders and Stroke (NS38073, R01NS030007, R01NS038073, NS 30007, NS01672)
- National Center for Research Resources (RR14661, S10RR014661)
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connexins and lens biology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
- Keywords
- astrocyte-neuron communication, calcium signaling, gap junctions, connexin 43, purinergic signaling, P2Y2 receptor, P2Y4 receptor, ATP, calcium waves, blood-brain barrier, brain endothelial cells, pericytes, blood flow regulation, water homeostasis
- MeSH terms
- Adenosine Triphosphate, Animals, Astrocytes, Basement Membrane, Blood-Brain Barrier, Brain, Cerebrovascular Circulation, Diffusion, Endothelium, Vascular, Fluorescent Dyes, Glial Fibrillary Acidic Protein, Male, Microcirculation, Rats, Sprague-Dawley, Gap Junctions, Connexin 43, Receptors, Purinergic P2, Patch-Clamp Techniques, Calcium Signaling, Pericytes, Rats, Receptors, Purinergic P2Y2, In Vitro Techniques
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