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Michael Alexander Dixon, Andrew Ian Jobling, Joanna Phipps, Samuel Alexander Mills, Erica L Fletcher; Functional microglial involvement in the neurovascular unit. Invest. Ophthalmol. Vis. Sci. 2019;60(9):1640.
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© ARVO (1962-2015); The Authors (2016-present)
To investigate the physiological role of microglial communication with inner retinal vasculature and to explore the mechanism of vasoregulation.
Immunohistochemistry was used to characterise the extent of microglial contact with neurons and inner retinal vasculature (IB4) in Cx3cr1+/GFP and Cx3cr1GFP/GFP transgenic mice in which one or both copies of the chemokine receptor Cx3cr1 are replaced with green fluorescent protein (GFP). Live cell confocal imaging of Cx3cr1+/GFP retinal explants was used to assess process motility of microglia in close contact with superficial capillaries. Microglia-mediated capillary response was evaluated in Dark Agouti rat retinal explants by measuring capillary diameter at areas of microglial contact while perfusing fractalkine (200ng/ml), a neuronally derived chemokine and sole ligand for Cx3cr1, in the presence and absence of the Angiotensin II receptor antagonist, candesartan (.227μM).
Results: Microglia make numerous physical connections with both blood vessels and synapses. The majority of inner retinal microglia in Cx3cr1+/GFP and Cx3cr1GFP/GFP retinae make contact with capillaries of the superficial vascular plexus (83 ± 1% versus 83 ± 1%, n=5, p>0.05). However, microglial density is increased in Cx3cr1GFP/GFP tissue (21 ± 3%, n=5, p<0.05). This results in an increase in the number of vessel-microglia contacts (19 ± 4%, n=5, p<0.05). Cx3cr1GFP/GFP microglia also display fewer branches per cell (-18 ± 4%, n=5, p<0.05) and accumulate in the subretinal space. Cx3cr1+ve cells making direct contact with inner retinal capillaries displayed no process motility over a duration of 20 mins (n=6 cells from 5 animals). Perfusing retinal explants with fractalkine evoked a constriction in capillaries that was reduced when explants were incubated with candesartan (-11 ± 3% baseline versus -2 ± 2% baseline, n=5-9, p<0.05).
Retinal microglia are involved in the neurovascular unit and regulate blood flow in response to fractalkine, a chemokine known to be released by neurons. Fractalkine-evoked capillary constriction is abolished in the presence of candesartan, suggesting angiotensin plays a role in microglia mediated vasoregulation.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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