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 suggests a significant role for high carbon dioxide (CO(2)) tension as well. Along these lines, although ischemia is often considered to be synonymous with an oxygen deficit, it is also associated with a concomitant local elevation of CO(2) that can lead to impaired developmental and ischemic neovascularization. The mechanisms by which hypercapnia induces retinal microvascular degeneration, a critical step which precedes the subsequent proliferative preretinal neovascularization, are not known. Nitrative stress has an important role in microvascular degeneration leading to ischemia in conditions such as ROP. Hypercapnia is a facilitator of nitration in vitro. We hereby present evidence that prolonged exposure to CO(2) impairs developmental retinal neovascularization 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, we demonstrate that an in vivo nitrative stress associated with retinal vasoobliteration results in nitration of arachidonic acids into trans-arachidonic acids (TAAs), which can act as mediators of nitrative stress by causing microvascular degeneration by inducing expression of the antiangiogenic factor thrombospondin-1. These recent findings establish a previously unexplored means by which hypercapnia hinders efficient neovascularization and provide new insight into the molecular mechanisms of nitrative stress on microvascular injury involving TAA, and suggest 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
Department of Pediatrics, Ophthalmology and Pharmacology, Research Center, Hôpital Ste-Justine, 3175 Ch. Côte-Sainte-Catherine, Montréal, Québec, Canada.
Kermorvant-Duchemin
Elsa
E
Checchin
Daniella
D
Sennlaub
Florian
F
Sirinyan
Mirna
M
Kooli
Amna
A
Lachapelle
Pierre
P
Chemtob
Sylvain
S
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D001928:Brain Diseases, Metabolic / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D003920:Diabetes Mellitus / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D006801:Humans; D006935:Hypercapnia / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D007231:Infant, Newborn; D007234:Infant, Premature; D009566:Nitrates / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D012162:Retinal Degeneration / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D015861:Retinal Neovascularization / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D012178:Retinopathy of Prematurity / Q000378:metabolism* / Q000473:pathology / Q000628:therapy
D009566:Nitrates; D016718:Arachidonic Acid; D010100:Oxygen