Microglia modulate the cerebrovascular reactivity through ectonucleotidase CD39
Abstract Microglia and the border-associated macrophages contribute to the modulation of cerebral blood flow, but the mechanisms have remained uncertain. Here, we show that microglia regulate the cerebral blood flow baseline and the responses to whisker stimulation or intra-cisternal magna injection...
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56093-5 |
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| author | Zhongxiao Fu Mallikarjunarao Ganesana Philip Hwang Xiao Tan Melissa Marie Kinkaid Yu-Yo Sun Emily Bian Aden Weybright Hong-Ru Chen Katia Sol-Church Ukpong B. Eyo Clare Pridans Francisco J. Quintana Simon C. Robson Pankaj Kumar B. Jill Venton Anne Schaefer Chia-Yi Kuan |
| author_facet | Zhongxiao Fu Mallikarjunarao Ganesana Philip Hwang Xiao Tan Melissa Marie Kinkaid Yu-Yo Sun Emily Bian Aden Weybright Hong-Ru Chen Katia Sol-Church Ukpong B. Eyo Clare Pridans Francisco J. Quintana Simon C. Robson Pankaj Kumar B. Jill Venton Anne Schaefer Chia-Yi Kuan |
| author_sort | Zhongxiao Fu |
| collection | DOAJ |
| description | Abstract Microglia and the border-associated macrophages contribute to the modulation of cerebral blood flow, but the mechanisms have remained uncertain. Here, we show that microglia regulate the cerebral blood flow baseline and the responses to whisker stimulation or intra-cisternal magna injection of adenosine triphosphate, but not intra-cisternal magna injection of adenosine in mice model. Notably, microglia repopulation corrects these cerebral blood flow anomalies. The microglial-dependent regulation of cerebral blood flow requires the adenosine triphosphate-sensing P2RY12 receptor and ectonucleotidase CD39 that initiates the dephosphorylation of extracellular adenosine triphosphate into adenosine in both male and female mice. Pharmacological inhibition or CX3CR1-CreER-mediated deletion of CD39 mimics the cerebral blood flow anomalies in microglia-deficient mice and reduces the upsurges of extracellular adenosine following whisker stimulation. Together, these results suggest that the microglial CD39-initiated breakdown of extracellular adenosine triphosphate co-transmitter is an important step in neurovascular coupling and the regulation of cerebrovascular reactivity. |
| format | Article |
| id | doaj-art-feda2772bb6c4a60af0253050a093bff |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-feda2772bb6c4a60af0253050a093bff2025-01-26T12:41:10ZengNature PortfolioNature Communications2041-17232025-01-0116111510.1038/s41467-025-56093-5Microglia modulate the cerebrovascular reactivity through ectonucleotidase CD39Zhongxiao Fu0Mallikarjunarao Ganesana1Philip Hwang2Xiao Tan3Melissa Marie Kinkaid4Yu-Yo Sun5Emily Bian6Aden Weybright7Hong-Ru Chen8Katia Sol-Church9Ukpong B. Eyo10Clare Pridans11Francisco J. Quintana12Simon C. Robson13Pankaj Kumar14B. Jill Venton15Anne Schaefer16Chia-Yi Kuan17Department of Neuroscience, Center for Brain Immunology and Glia, University of Virginia School of MedicineDepartment of Chemistry, University of VirginiaNash Family Department of Neuroscience, Icahn School of Medicine at Mount SinaiDepartment of Neuroscience, Center for Brain Immunology and Glia, University of Virginia School of MedicineDepartment of Neuroscience, Center for Brain Immunology and Glia, University of Virginia School of MedicineInstitute of BioPharmaceutical Sciences, National Sun Yat-sen UniversityDepartment of Neuroscience, Center for Brain Immunology and Glia, University of Virginia School of MedicineDepartment of Neuroscience, Center for Brain Immunology and Glia, University of Virginia School of MedicineDepartment of Life Sciences and Institute of Genome Sciences, National Yang Ming Chiao Tung UniversityDepartment of Pathology, School of Medicine, University of VirginiaDepartment of Neuroscience, Center for Brain Immunology and Glia, University of Virginia School of MedicineCentre for Inflammation Research, Institute for Regeneration and Repair, The University of EdinburghAnn Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical SchoolDepartments of Anesthesia and Medicine, Beth Israel Deaconess Medical Center, Harvard Medical SchoolDepartment of Biochemistry and Molecular Genetics, University of Virginia School of MedicineDepartment of Chemistry, University of VirginiaNash Family Department of Neuroscience, Icahn School of Medicine at Mount SinaiDepartment of Neuroscience, Center for Brain Immunology and Glia, University of Virginia School of MedicineAbstract Microglia and the border-associated macrophages contribute to the modulation of cerebral blood flow, but the mechanisms have remained uncertain. Here, we show that microglia regulate the cerebral blood flow baseline and the responses to whisker stimulation or intra-cisternal magna injection of adenosine triphosphate, but not intra-cisternal magna injection of adenosine in mice model. Notably, microglia repopulation corrects these cerebral blood flow anomalies. The microglial-dependent regulation of cerebral blood flow requires the adenosine triphosphate-sensing P2RY12 receptor and ectonucleotidase CD39 that initiates the dephosphorylation of extracellular adenosine triphosphate into adenosine in both male and female mice. Pharmacological inhibition or CX3CR1-CreER-mediated deletion of CD39 mimics the cerebral blood flow anomalies in microglia-deficient mice and reduces the upsurges of extracellular adenosine following whisker stimulation. Together, these results suggest that the microglial CD39-initiated breakdown of extracellular adenosine triphosphate co-transmitter is an important step in neurovascular coupling and the regulation of cerebrovascular reactivity.https://doi.org/10.1038/s41467-025-56093-5 |
| spellingShingle | Zhongxiao Fu Mallikarjunarao Ganesana Philip Hwang Xiao Tan Melissa Marie Kinkaid Yu-Yo Sun Emily Bian Aden Weybright Hong-Ru Chen Katia Sol-Church Ukpong B. Eyo Clare Pridans Francisco J. Quintana Simon C. Robson Pankaj Kumar B. Jill Venton Anne Schaefer Chia-Yi Kuan Microglia modulate the cerebrovascular reactivity through ectonucleotidase CD39 Nature Communications |
| title | Microglia modulate the cerebrovascular reactivity through ectonucleotidase CD39 |
| title_full | Microglia modulate the cerebrovascular reactivity through ectonucleotidase CD39 |
| title_fullStr | Microglia modulate the cerebrovascular reactivity through ectonucleotidase CD39 |
| title_full_unstemmed | Microglia modulate the cerebrovascular reactivity through ectonucleotidase CD39 |
| title_short | Microglia modulate the cerebrovascular reactivity through ectonucleotidase CD39 |
| title_sort | microglia modulate the cerebrovascular reactivity through ectonucleotidase cd39 |
| url | https://doi.org/10.1038/s41467-025-56093-5 |
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