Journal Article

Fractalkine-induced microglial vasoregulation occurs within the retina and is altered early in diabetic retinopathy

Phipps, Joanna A., Young, James C., Dixon, Michael A., Ivanova, Elena, Jobling, Andrew I., Sagdullaev, Botir T., Fletcher, Erica L., Wong, Vickie H. Y., Greferath, Ursula, Venables, Gene, Hui, Flora, Vessey, Kirstan A., Bui, Bang V., Mills, Samuel A., Tonc, Josh, He, Zheng, Wong, Connie H. Y.

2021

Overview

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.

• Publisher: National Academy of Sciences
• Subject: Angiotensin / Angiotensinogen / Animals / Astrocytes / Benzimidazoles - pharmacology / Biological Sciences / Biphenyl Compounds - pharmacology / Blood flow / Blood vessels / Brain / Capillaries / Cell Biology / Central nervous system / Chemokine CX3CL1 - metabolism / Chemokine CX3CL1 - pharmacology / Constrictions / CX3CR1 protein / Diabetes / Diabetes mellitus / Diabetic retinopathy / Diabetic Retinopathy - chemically induced / Diabetic Retinopathy - metabolism / Diabetic Retinopathy - pathology / Explants / Flow control / Fractalkine / Functional analysis / Gene Expression Profiling / Glia / Immune system / Mice / Microglia / Microglia - metabolism / Microglia - physiology / Monocytes / Mueller cells / Neuronal-glial interactions / Neurons - physiology / Pericytes - pathology / Rats / Renin / Renin-Angiotensin System - drug effects / Renin-Angiotensin System - genetics / Retina / Retina - metabolism / Retina - pathology / Retinal Vessels - drug effects / Retinal Vessels - pathology / Retinopathy / Signal Transduction - drug effects / Streptozocin / Streptozocin - pharmacology / Synapses / Tetrazoles - pharmacology / Transcriptomes / Vasoactive agents / Vasoconstriction - drug effects