Chemtob S: Potential role of microglia in retinal blood vessel formation. Invest Ophthalmol Vis Sci 2006

PURPOSE. The role of microglia, present in the retina early in development before vascularization, remains ill defined. The authors investigated whether microglia are implicated in retinal blood vessel formation. METHODS. The microglia and vasculature of developing human fetal and rodent retinas were examined by labeling the endothelial cells with lectin and the microglia with CD18 antibody or green fluorescent protein driven by the promoter of the chemokine receptor CX 3 CR1. Rodent ischemic proliferative retinopathy induced by hyperoxia or hypercapnia, which model retinopathy of prematurity, and ex vivo retinal explants were used to assess microglial involvement in vascular pathology. Microglial participation in developmental retinal vessel formation was further studied in neonatal rats after pharmacologic macrophage depletion with the use of clodronate liposomes and subsequent intravitreal injection of microglia. RESULTS. Microglia intimately appose developing vessels of human and murine retinas. Ischemic retinopathy models exhibit decreased microglia concomitant with the characteristic reductions in vasculature observed in these retinopathies. Retinal explants exposed to conditions resulting in ischemic retinopathies (in vivo) reveal that antioxidants protect against microglial loss. Depletion of resident retinal microglia, but not systemic macrophages, reduced developmental vessel growth and density, which were restored by intravitreal microglial injection. CONCLUSIONS. These observations suggest that proper retinal blood vessel formation requires an adequate resident microglial population because diminished microglia are associated with decreased vascularity in models of ischemic retinopathy and retinal vascular development. In light of these findings, the traditional definition of microglia as merely immunocompetent cells should be reconsidered to encompass this new function related to blood vessel formation. (Invest Ophthalmol Vis Sci

La rétinopathie du prématuré

L’exposition à des concentrations élevées d’oxygène est une cause majeure de la rétinopathie du prématuré ; elle est caractérisée par une dégénérescence des micro-vaisseaux et par une ischémie rétinienne suivie d’une angiogenèse anarchique pré-rétinienne. Cependant, des données cliniques et expérimentales suggèrent que des concentrations élevées de dioxyde de carbone joueraient un rôle important dans cette pathologie. L’hyperoxie et l’hypercapnie sont associées au déclenchement d’un stress azoté qui favorise la nitration de l’acide arachidonique qui se transforme en acide trans-arachidonique. À son tour l’acide trans-arachidonique peut lui-même causer une dégénérescence micro-vasculaire dans la rétine par suite de l’induction de l’expression du facteur anti-angiogénique thrombospondine-1. Ces effets nouvellement décrits du stress azoté menant à des dommages micro-vasculaires et impliquant l’acide trans-arachidonique ouvrent peut-être de nouvelles avenues pour le traitement des affections liées au stress azoté comme les rétinopathies (autant celles des prématurés que des diabétiques) et les encéphalopathies ischémiques

Hypercapnia prevents neovascularization via nitrative stress.

Neovascularization after an ischemic insult is a beneficial attempt to salvage the injured tissue. Yet, despite the production of angiogenic factors within ischemic tissues, compensatory growth of new vessels fails to provide adequate vascularization. Thus, we hypothesized that local factors counter efficient revascularization. Whereas ischemia is often considered to be synonymous with an oxygen deficit, it is also associated with a concomitant local elevation of carbon dioxide (CO2). Although studies suggest that hypercapnia impacts tissue neovascularization, its significance relative to the abundantly described effects of hypoxia and its underlying mechanisms have yet to be elucidated. Therefore, we investigated the effects of hypercapnia on blood vessel growth in models of developmental and ischemic neovascularization. Acute and prolonged CO2 exposure inhibited developmental neovascularization of the rodent retina, as well as revascularization of the ischemic retina. Hypercapnia induced early increases in endothelial nitric oxide synthase and nitrative stress, associated with astrocyte impairment and endothelial cell death, as well as downregulation of the proangiogenic prostaglandin E2 receptor EP3. These results establish a previously unexplored means by which hypercapnia hinders efficient neovascularization, a mechanism that may contribute to ischemic tissue injury