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Fractalkine-induced microglial vasoregulation occurs within the retina and is altered early in diabetic retinopathy.
Mills, Samuel A; Jobling, Andrew I; Dixon, Michael A; Bui, Bang V; Vessey, Kirstan A; Phipps, Joanna A; Greferath, Ursula; Venables, Gene; Wong, Vickie H Y; Wong, Connie H Y; He, Zheng; Hui, Flora; Young, James C; Tonc, Josh; Ivanova, Elena; Sagdullaev, Botir T; Fletcher, Erica L.
Affiliation
  • Mills SA; Department of Anatomy and Physiology, University of Melbourne, Parkville, 3010 VIC, Australia.
  • Jobling AI; Department of Anatomy and Physiology, University of Melbourne, Parkville, 3010 VIC, Australia.
  • Dixon MA; Department of Anatomy and Physiology, University of Melbourne, Parkville, 3010 VIC, Australia.
  • Bui BV; Department of Optometry and Vision Sciences, University of Melbourne, Parkville, 3010 VIC, Australia.
  • Vessey KA; Department of Anatomy and Physiology, University of Melbourne, Parkville, 3010 VIC, Australia.
  • Phipps JA; Department of Anatomy and Physiology, University of Melbourne, Parkville, 3010 VIC, Australia.
  • Greferath U; Department of Anatomy and Physiology, University of Melbourne, Parkville, 3010 VIC, Australia.
  • Venables G; Department of Anatomy and Physiology, University of Melbourne, Parkville, 3010 VIC, Australia.
  • Wong VHY; Department of Optometry and Vision Sciences, University of Melbourne, Parkville, 3010 VIC, Australia.
  • Wong CHY; Department of Medicine, Centre for Inflammatory Diseases, School of Clinical Sciences, Monash University, Clayton, 3800 VIC, Australia.
  • He Z; Department of Optometry and Vision Sciences, University of Melbourne, Parkville, 3010 VIC, Australia.
  • Hui F; Department of Optometry and Vision Sciences, University of Melbourne, Parkville, 3010 VIC, Australia.
  • Young JC; Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, 3002 VIC, Australia.
  • Tonc J; Department of Anatomy and Physiology, University of Melbourne, Parkville, 3010 VIC, Australia.
  • Ivanova E; Department of Anatomy and Physiology, University of Melbourne, Parkville, 3010 VIC, Australia.
  • Sagdullaev BT; Burke Neurological Institute, Weill Cornell Medical College, White Plains, NY 10605.
  • Fletcher EL; Burke Neurological Institute, Weill Cornell Medical College, White Plains, NY 10605.
Proc Natl Acad Sci U S A ; 118(51)2021 12 21.
Article in En | MEDLINE | ID: mdl-34903661
ABSTRACT
Local blood flow control within the central nervous system (CNS) is critical to proper function and is dependent on coordination between neurons, glia, and blood vessels. Macroglia, such as astrocytes and Müller cells, contribute to this neurovascular unit within the brain and retina, respectively. This study explored the role of microglia, the innate immune cell of the CNS, in retinal vasoregulation, and highlights changes during early diabetes. Structurally, microglia were found to contact retinal capillaries and neuronal synapses. In the brain and retinal explants, the addition of fractalkine, the sole ligand for monocyte receptor Cx3cr1, resulted in capillary constriction at regions of microglial contact. This vascular regulation was dependent on microglial Cx3cr1 involvement, since genetic and pharmacological inhibition of Cx3cr1 abolished fractalkine-induced constriction. Analysis of the microglial transcriptome identified several vasoactive genes, including angiotensinogen, a constituent of the renin-angiotensin system (RAS). Subsequent functional analysis showed that RAS blockade via candesartan abolished microglial-induced capillary constriction. Microglial regulation was explored in a rat streptozotocin (STZ) model of diabetic retinopathy. Retinal blood flow was reduced after 4 wk due to reduced capillary diameter and this was coincident with increased microglial association. Functional assessment showed loss of microglial-capillary response in STZ-treated animals and transcriptome analysis showed evidence of RAS pathway dysregulation in microglia. While candesartan treatment reversed capillary constriction in STZ-treated animals, blood flow remained decreased likely due to dilation of larger vessels. This work shows microglia actively participate in the neurovascular unit, with aberrant microglial-vascular function possibly contributing to the early vascular compromise during diabetic retinopathy.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Retina / Microglia / Diabetic Retinopathy / Chemokine CX3CL1 Limits: Animals Language: En Journal: Proc Natl Acad Sci U S A Year: 2021 Document type: Article Affiliation country: Australia
Fulltext
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Retina / Microglia / Diabetic Retinopathy / Chemokine CX3CL1 Limits: Animals Language: En Journal: Proc Natl Acad Sci U S A Year: 2021 Document type: Article Affiliation country: Australia