Glial Cell Calcium Signaling Mediates Capillary Regulation of Blood Flow in the Retina.
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.



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.
Department of Neuroscience, University of Minnesota Twin Cities, Minneapolis, Minnesota 55455, and.
Kyle R
0000-0002-2502-6202
KR
Biesecker
Department of Neuroscience, University of Minnesota Twin Cities, Minneapolis, Minnesota 55455, and.
Anja I
0000-0003-1038-2156
AI
Srienc
Department of Neuroscience, University of Minnesota Twin Cities, Minneapolis, Minnesota 55455, and.
Angela M
AM
Shimoda
Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Amit
0000-0001-7948-4498
A
Agarwal
Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Dwight E
0000-0002-7133-7378
DE
Bergles
Department of Neuroscience, University of Minnesota Twin Cities, Minneapolis, Minnesota 55455, and.
Paulo
P
Kofuji
Department of Neuroscience, University of Minnesota Twin Cities, Minneapolis, Minnesota 55455, and ean@umn.edu.
Eric A
0000-0002-9296-6237
EA
Newman
D000818:Animals; D000941:Antigens / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000235:genetics / Q000502:physiology*; D002196:Capillaries / Q000187:drug effects / Q000502:physiology*; D063928:Ependymoglial Cells / Q000187:drug effects / Q000502:physiology*; D027341:Excitatory Amino Acid Transporter 1 / Q000235:genetics / Q000378:metabolism; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006025:Glycosaminoglycans / Q000502:physiology; D066298:In Vitro Techniques; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000235:genetics / Q000378:metabolism; D060850:LIM-Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011509:Proteoglycans / Q000378:metabolism; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology*; D012160:Retina / Q000166:cytology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014795:Visual Pathways / Q000502:physiology; D000099216:Chondroitin Sulfate Proteoglycan 4
D000941:Antigens; D002118:Calcium; D027341:Excitatory Amino Acid Transporter 1; D005904:Glial Fibrillary Acidic Protein; D006025:Glycosaminoglycans; D053496:Inositol 1,4,5-Trisphosphate Receptors; D060850:LIM-Homeodomain Proteins; D011509:Proteoglycans; D014157:Transcription Factors; D000099216:Chondroitin Sulfate Proteoglycan 4; C580990:Ip3r2 protein, mouse; C493393:Slc1a3 protein, mouse; C063843:insulin gene enhancer binding protein Isl-1; C007858:glucuronyl glucosamine glycan sulfate
blood flow; calcium signaling; capillary; glia; neurovascular coupling; retina