Oxidants, nitric oxide and prostanoids in the developing ocular vasculature: a basis for ischemic retinopathy.
The choroid is the main source of oxygen to the retina. In contrast to the adult, the absence of autoregulation of choroidal blood flow in the newborn leads to hyperoxygenation of the retina. In the immature retina which contains relatively low levels of antioxidants this hyperoxygenation favors peroxidation including the generation of biologically active isoprostanes, and results in vasoconstriction and vascular cytotoxicity leading to ischemia, which predisposes to the development of a vasoproliferative retinopathy, commonly termed retinopathy of prematurity. During frequently encountered oxidative stress to the perinate, the combined absence of vascular autoregulation and excessive oxygen delivery to the eyes of the developing subject is largely the result of a complex epigenetic and genetic interplay between prostanoids and nitric oxide (NO) systems on vasomotor regulation. The effects of certain prostaglandins are NO-dependent; conversely, those of NO have also been found to be largely prostaglandin I(2)-mediated in the eye; and NO synthase expression seems to be significantly regulated by other prostaglandins apparently through activation of functional perinuclear prostanoid receptors which affect gene transcription. The increased production of both prostaglandins and NO in the perinate augment ocular blood flow and as a result oxygen delivery to an immature retina partly devoid of antioxidant defenses. The ensuing peroxidation results in impaired circulation (partly thromboxane A(2)-dependent) and vascular integrity, leading to ischemia which predisposes to abnormal preretinal neovascularization, a major feature of ischemic retinopathy. Because tissue oxygenation is largely dependent upon circulation and critical in the generation of reactive oxygen species, and since the latter exert a major contribution in the pathogenesis of retinopathy of prematurity, it is important to understand the mechanisms that govern ocular blood flow. In this review we focus on the important and complex interaction between prostanoid, NO and peroxidation products on circulatory control of the immature retina.
Hardy
P
P
Departments of Pediatrics, Ophthalmology and Pharmacology, Centre de Recherche de l'Hôpital Sainte-Justine, Quebec, H3T 1C5, Montreal, Canada.
Dumont
I
I
Bhattacharya
M
M
Hou
X
X
Lachapelle
P
P
Varma
D R
DR
Chemtob
S
S
D002829:Choroid / Q000098:blood supply; D015237:Dinoprost / Q000378:metabolism*; D016228:Endothelial Growth Factors / Q000378:metabolism; D005609:Free Radicals / Q000378:metabolism; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature / Q000378:metabolism; D007511:Ischemia / Q000378:metabolism; D015227:Lipid Peroxidation; D008222:Lymphokines / Q000378:metabolism; D009389:Neovascularization, Pathologic; D009566:Nitrates / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000378:metabolism; D012160:Retina / Q000378:metabolism*; D012171:Retinal Vessels; D012178:Retinopathy of Prematurity / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D005609:Free Radicals; D008222:Lymphokines; D009566:Nitrates; D018078:Receptors, Prostaglandin E; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C039642:peroxynitric acid; D009569:Nitric Oxide; D015237:Dinoprost; D019001:Nitric Oxide Synthase; D010100:Oxygen