Oxidants, nitric oxide and prostanoids in the developing ocular vasculature: a basis for ischemic retinopathy

Abstract

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.

Antenatal antioxidant prevents adult hypertension, vascular dysfunction, and microvascular rarefaction associated with in utero exposure to a low-protein diet

“…Immature animals exhibit increased vulnerability to microvascular oxidant stress-induced injury (especially the endothelial cells) (8,35). Vasoconstriction and endothelial cell damage lead to degenerative processes in terminal arterioles and capillaries inducing anatomical rarefaction (24,76). Decrease in NO bioavailability by ROS scavenging could also interfere with angiogenesis (34).…”

Oxygen Toxicity and Reactive Oxygen Species: The Devil Is in the Details

“…After birth, the marked increase in systemic oxygen tensions in the preterm newborn suppresses VEGF production. This occurs in conjunction with impairment in autoregulation of retinal blood flow as well as a relative deficiency of antioxidants in the immature retina (31). In the absence of VEGF (and other factors), angiogenic budding stops, and apoptosis of developing vessels occurs secondary to the formation of reactive oxygen and nitrogen species (32)(33)(34).…”

Neonatal Oxygen Exposure in Rats Leads to Cardiovascular and Renal Alterations in Adulthood

“…Evidence in humans and animal studies indicate that premature newborns are more susceptible to oxidative tissue damage, leading to pathologies such as retinopathy of prematurity and bronchopulmonary dysplasia. 3,4 However, the long-term vascular and blood pressure consequences of neonatal hyperoxic injury are unknown.It is becoming increasingly evident that conditions early in life can influence adult diseases; however, the mechanisms are incompletely understood. 5,6 Recent data suggest that perinatal oxidative stress may be the initiating trigger in long-term programming of cardiovascular function.…”