SYSTEMIC INFLAMMATORY STRESS PROVOKES ABNORMAL RETINAL VASCULAR DEVELOPMENT

Abstract

Purpose: Perinatal inflammatory stress in preterm babies is associated with increased rates of severe retinopathy of prematurity (ROP) and adverse neurological dysfunction. While sustained perinatal systemic inflammation is known to perturb and damage the cerebral neurovascular unit, the impact on the neurovascular retina remains ill-defined. In this study, we set out to determine the consequences of severe systemic inflammatory stress on developmental retinal vascularization and evaluate the subsequent outcome on retinal function in later life.

Methods: We induced systemic inflammatory stress in C57BL/6 mouse pups by an intraperitoneal injection of LPS (1 mg/kg) at post-natal day 4. A detailed and systematic analysis of retinal microglial infiltration, retinal vascular morphology, density and growth rate was performed at key time-points throughout development of retinal vascularization (P6, P8, P10 and P21). Electroretinography was performed 6 weeks post-induction of inflammatory stress to evaluate retinal function in adult life.

Results: Systemic inflammatory stress had an immediate impact on retinal vascular development. As early as 48 hours after treatment with LPS, vascular densities were significantly increased by over 1.5-fold in both peripheral and central zones of the retina. A major increase in microglial cell number and activation was noted and mostly observed in the outer plexiform layers prior to central and peripheral retinal vascularization. In addition, their physical contact with sprouting vessels suggest that microglia partake in promoting the observed aberrant retinal vascularization persisting until P21. The impact of perinatal inflammatory stress was sustained in mature animals which displayed depleted retinal vascular beds and had significantly decreased retinal function as determined by electroretinogram.

Conclusions: Our data reveal that early severe post-natal inflammatory stress leads to abnormal retinal vascular development and ultimately, compromises permanently retinal function. The aberrant and exaggerated retinal vascularization observed is associated with microglial cell activation, providing a mechanism for perinatal sepsis-associated predisposition to ROP. Attenuation in microglial activation should be protective to the immature newborn retina.

Keywords: 698 retinal development • 706 retinopathy of prematurity • 557 inflammation