Abstract
Purpose: :
Proliferative retinal neovascularization induced by ischemia is a feature of many retinal diseases. Retinal microglia can influence pathological neovascularization, likely through an exchange of cellular signals with associated vascular elements. CX3CR1 is a chemokine receptor located specifically on microglia; its ligand, CX3CL1 displays pro-angiogenic activity both in vivo and in vitro. We aim to discover the regulatory role, if any, of CX3CR1 signaling in ischemic retinopathy and clarify the molecular nature of microglial-vascular interactions.
Methods: :
Ischemic vascular changes were compared in transgenic mice in which CX3CR1 signaling was either preserved or ablated. Using the oxygen-induced retinopathy (OIR) model, we induced ischemic retinopathy in transgenic mice in which the gene for CX3CR1 has been replaced by green fluorescent protein (GFP) and their wild type controls. CX3CR1+/+, CX3CR1+/GFP, and CX3CR1GFP/GFP transgenic mice were exposed to 75% oxygen for 5 days starting from postnatal day (P) 7, and then transferred back to room air. At P12 and P17, the extents of vascular repair and neovascularization, associated changes in retinal microglia distribution, ischemic neuronal cell loss, were quantified and compared.
Results: :
We found that: (1) CX3CR1 signaling is not required for normal vascular, microglial, and neuronal development in the retina in the first postnatal week, (2) the processes of retinal vascular repair and neovascularization following ischemia occur similarly with and without CX3CR1 signaling, (3) microglia redistribution in the retina and their association with vascular elements occurring concurrently is independent of CX3CR1, and (4) CX3CR1 does not influence the extent of neuronal cell loss in the retina following ischemia.
Conclusions: :
Regulatory signals exchanged between microglia and vascular elements in the ischemic retinopathy animal model are unlikely to involve CX3CR1. These results have implications on therapeutic approaches to pathological neovascularization involving the modulation of chemokine signaling in general, and the regulation of CX3CR1 signaling specifically.
Keywords: retinopathy of prematurity • microglia • neovascularization