[Hypercapnia- and trans-arachidonic acid-induced retinal microvascular degeneration: implications in the genesis of retinopathy of prematurity].
High oxygen tension is a major factor in the genesis of retinopathy of prematurity (ROP). However, clinical and experimental evidence also suggest a significant role for high levels of carbon dioxide (CO(2)). Hypercapnia is a facilitator of nitration in vitro, and nitrative stress is known to have an important role in microvascular degeneration leading to ischemia in conditions such as ROP. We hereby present evidence that prolonged exposure to CO(2) impairs developmental retinal neovascularisation through a mechanism involving increased endothelial nitric oxide synthase and induction of a nitrative stress; effects of hypercapnia are independent of its hyperaemic effects. Moreover, in a model of oxygen-induced retinopathy, we demonstrate that an in vivo nitrative stress associated with retinal vasoobliteration results in nitration of cis-arachidonic acids into trans-arachidonic acids (TAAs). TAAs act in turn as mediators of nitrative stress by causing microvascular degeneration by inducing expression of the anti-angiogenic factor thrombospondin-1. These recent findings establish a previously unexplored means by which hypercapnia hinders efficient neovascularisation and provide new insight into the molecular mechanisms of nitrative stress on microvascular injury involving TAA, therefore opening new therapeutic avenues in the management of nitrative stress disorders such as in ischemic retinopathies (of prematurity and of diabetes) and encephalopathies.
Leduc
Martin
M
Départements de Pédiatrie, d'Ophtalmologie et de Pharmacologie, Centre de recherche, CHU Sainte-Justine, Montréal, Québec, H3T 1C5 Canada.
Kermorvant-Duchemin
Elsa
E
Checchin
Daniella
D
Sennlaub
Florian
F
Chemtob
Sylvain
S
D016718:Arachidonic Acid / Q000633:toxicity; D006801:Humans; D006935:Hypercapnia / Q000503:physiopathology; D007231:Infant, Newborn; D007234:Infant, Premature; D008833:Microcirculation / Q000502:physiology; D012162:Retinal Degeneration / Q000139:chemically induced / Q000196:embryology* / Q000503:physiopathology*
D016718:Arachidonic Acid