Capillary-associated microglia regulate vascular structure and function through PANX1-P2RY12 coupling
Capillary-associated microglia regulate vascular structure and function through PANX1-P2RY12 coupling
Abstract Microglia are brain-resident immune cells with a repertoire of functions in the developing, mature and pathological brain. Their wide-ranging roles in physiology include the clearance of cellular debris, elimination of excess synapses, regulation of neuronal activity and contributions to blood vessel development. Despite these known roles for microglia, the extent of their interactions with the vasculature and potential regulation of vascular physiology has been insufficiently explored. Here, using in vivo acute and longitudinal two-photon imaging in transgenic mice combined with electron microscopy, fixed tissue immunohistochemistry, pharmacological treatments and laser speckle imaging, we document the steady-state interactions between ramified CX3CR1+ myeloid cell somata and capillaries in the brain. We first confirm that these myeloid cells are bona fide microglia by molecular, morphological and ultrastructural approaches. Then we give a detailed spatio-temporal characterization of these capillary-associated microglia (CAMs) comparing and contrasting them with parenchymal microglia (PCMs) in their static, dynamic and chronic morphological activities including during microglial depletion and repopulation. Molecularly, we identify microglial-specific purinergic P2RY12 receptors as a receptor regulating CAM interactions under the control of released purines from pannexin 1 (PANX1) channels. Furthermore, to elucidate roles for microglia in vascular structure and function, we eliminated microglia and showed that this triggered capillary dilation, blood flow increase, and impaired vasodilative responses. We find that P2RY12?/? and PANX1?/? mice recapitulate these vascular impairments suggesting purines released through PANX1 channels play important roles in activating microglial P2RY12 receptors to regulate neurovascular structure and function.
Isakson Brant E.、Bisht Kanchan、Sharma Kaushik、Lentferink Dennis H.、Chen Hong-Ru、Calcuttawala Zainab、Corliss Bruce、Jabbour Lara、Eyo Ukpong B.、Benderoth Jordan、Kuan Chia-Yi、Sun Yu-Yo、Tremblay Marie-¨¨ve、Uweru Joseph O.、Campos-Salazar Antony Brayan、Amancherla Saipranusha、Okojie Kenneth A.、Friestad Bria、Mills William A. III
Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine||Department of Molecular Physiology and Biophysics, University of Virginia School of MedicineDepartment of Neuroscience, University of Virginia School of Medicine||Center for Brain Immunology and Glia, University of VirginiaDepartment of Neuroscience, University of Virginia School of Medicine||Center for Brain Immunology and Glia, University of VirginiaDepartment of Neuroscience, University of Virginia School of Medicine||Center for Brain Immunology and Glia, University of VirginiaDepartment of Neuroscience, University of Virginia School of Medicine||Center for Brain Immunology and Glia, University of VirginiaDepartment of Neuroscience, University of Virginia School of MedicineRobert M. Berne Cardiovascular Research Center, University of Virginia School of MedicineDepartment of Neuroscience, University of Virginia School of MedicineDepartment of Neuroscience, University of Virginia School of Medicine||Center for Brain Immunology and Glia, University of Virginia||Robert M. Berne Cardiovascular Research Center, University of Virginia School of MedicineDepartment of Neuroscience, University of Virginia School of MedicineDepartment of Neuroscience, University of Virginia School of Medicine||Center for Brain Immunology and Glia, University of VirginiaDepartment of Neuroscience, University of Virginia School of Medicine||Center for Brain Immunology and Glia, University of VirginiaAxe Neurosciences, Centre de recherche du CHU de Qu¨|bec - Universit¨| Laval||D¨|partement de m¨|decine mol¨|culaire, Universit¨| Laval||Department of Neurology and Neurosurgery, McGill University||Division of Medical Sciences, University of Victoria||Biochemistry and Molecular Biology, Faculty of Medicine, The University of British ColombiaDepartment of Neuroscience, University of Virginia School of Medicine||Center for Brain Immunology and Glia, University of VirginiaDepartment of Neuroscience, University of Virginia School of Medicine||Center for Brain Immunology and Glia, University of VirginiaDepartment of Neuroscience, University of Virginia School of MedicineDepartment of Neuroscience, University of Virginia School of Medicine||Center for Brain Immunology and Glia, University of VirginiaDepartment of Neuroscience, University of Virginia School of Medicine||Center for Brain Immunology and Glia, University of VirginiaDepartment of Neuroscience, University of Virginia School of Medicine||Center for Brain Immunology and Glia, University of Virginia||Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine
基础医学细胞生物学生理学
Isakson Brant E.,Bisht Kanchan,Sharma Kaushik,Lentferink Dennis H.,Chen Hong-Ru,Calcuttawala Zainab,Corliss Bruce,Jabbour Lara,Eyo Ukpong B.,Benderoth Jordan,Kuan Chia-Yi,Sun Yu-Yo,Tremblay Marie-¨¨ve,Uweru Joseph O.,Campos-Salazar Antony Brayan,Amancherla Saipranusha,Okojie Kenneth A.,Friestad Bria,Mills William A. III.Capillary-associated microglia regulate vascular structure and function through PANX1-P2RY12 coupling[EB/OL].(2025-03-28)[2025-05-14].https://www.biorxiv.org/content/10.1101/2021.08.02.454769.点此复制
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