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Glial Cell Calcium Signaling Mediates Capillary Regulation of Blood Flow in the Retina
Open accessAbstract
The brain is critically dependent on the regulation of blood flow to nourish active neurons. One widely held hypothesis of blood flow regulation holds that active neurons stimulate Ca 2+ increases in glial cells, triggering glial release of vasodilating agents. This hypothesis has been challenged, as arteriole dilation can occur in the absence of glial Ca 2+ signaling. We address this controversy by imaging glial Ca 2+ signaling and vessel dilation in the mouse retina. We find that sensory stimulation results in Ca 2+ increases in the glial endfeet contacting capillaries, but not arterioles, and that capillary dilations often follow spontaneous Ca 2+ signaling. In IP3R2 −/− mice, where glial Ca 2+ signaling is reduced, light-evoked capillary, but not arteriole, dilation is abolished. The results show that, independent of arterioles, capillaries actively dilate and regulate blood flow. Furthermore, the results demonstrate that glial Ca 2+ signaling regulates capillary but not arteriole blood flow. SIGNIFICANCE STATEMENT We show that a Ca 2+ -dependent glial cell signaling mechanism is responsible for regulating capillary but not arteriole diameter. This finding resolves a long-standing controversy regarding the role of glial cells in regulating blood flow, demonstrating that glial Ca 2+ signaling is both necessary and sufficient to dilate capillaries. While the relative contributions of capillaries and arterioles to blood flow regulation remain unclear, elucidating the mechanisms that regulate capillary blood flow may ultimately lead to the development of therapies for treating diseases where blood flow regulation is disrupted, including Alzheimer's disease, stroke, and diabetic retinopathy. This finding may also aid in revealing the underlying neuronal activity that generates BOLD fMRI signals.
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“These findings coupled by recent physiological experiments on pericyte contractility support that pericytes play an active role in regulating CBF (65, 173, 228, 318, 319, 470).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [65]
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Metadata
- Authors
- Biesecker, K. R., Srienc, A. I., Shimoda, A. M., Agarwal, A., Bergles, D. E., Kofuji, P., & Newman, E. A.
- Affiliations
- University of Minnesota (US)
- Johns Hopkins University (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2016-09-07
- Volume
- 36
- Issue
- 36
- Pages
- 9435-9445
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC5013190
- OpenAlex
- W2516254780
- Cited by
- 144
- References
- 57
- Citations by year
- 2026: 6 · 2025: 13 · 2024: 10 · 2023: 15 · 2022: 19 · 2021: 23 · 2020: 11 · 2019: 10 · 2018: 19 · 2017: 16 · 2016: 2
- FWCI
- 8.58
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (UL1TR000114, NS050274)
- National Institute of Mental Health (P50MH100024, P50MH084020)
- National Eye Institute (R01EY026882, R01EY004077, R01EY026514, P30EY011374)
- National Institute of General Medical Sciences (T32GM008471)
- National Institute of Neurological Disorders and Stroke (P30NS050274)
- National Institute of Dental and Craniofacial Research (T90DE022732)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- retinal capillaries, arterioles, IP3R2, sensory stimulation, vasodilation, BOLD fMRI, diabetic retinopathy, stroke
- MeSH terms
- Chondroitin Sulfate Proteoglycan 4, Animals, Antigens, Calcium, Capillaries, Female, Glial Fibrillary Acidic Protein, Glycosaminoglycans, Male, Mice, Inbred C57BL, Mice, Transgenic, Proteoglycans, Regional Blood Flow, Retina, Transcription Factors, Visual Pathways, Calcium Signaling, Excitatory Amino Acid Transporter 1, Mice, Inositol 1,4,5-Trisphosphate Receptors, LIM-Homeodomain Proteins, Ependymoglial Cells, In Vitro Techniques
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