Attenuation of Retinal Vascular Development in Neonatal Mice Subjected to Hypoxic-Ischemic Encephalopathy

Abstract

A significant proportion of children that survive hypoxic-ischemic encephalopathy (HIE) develop visual impairment. These visual deficits are generally attributed to injuries that occur in the primary visual cortex and other visual processing systems. Recent studies suggested that neuronal damage might also occur in the retina. An important structure affecting the viability of retinal neurons is the vasculature. However, the effects of HIE on the retinal neurovasculature have not been systemically evaluated. Here we investigated whether exposure of postnatal day 9 (P9) neonatal mice to HIE is sufficient to induce neurovascular damage in the retina. We demonstrate that the blood vessels on the surface of the retina, from mice subjected to HIE, were abnormally enlarged with signs of degeneration. The intermediate and deep vascular layers in these retinas failed to form normally, particularly in the periphery. All the vascular damages observed here were irreversible in nature up to 100 days post HIE. We also observed loss of retinal neurons, together with changes in both astrocytes and Müller cells mainly in the inner retina at the periphery. Collectively, our findings suggest that HIE results in profound alterations in the retinal vasculature, indicating the importance of developing therapeutic strategies to protect neurovascular dysfunction not only in the brain but also in the retina for infants exposed to HIE.

TRPV1 mediates astrocyte activation and interleukin-1β release induced by hypoxic ischemia (HI)

“…A well-characterized model of neonatal HI was followed as a previously described [2, 37]. P9 C57BL/6 WT and TRPV1 KO mice of both genders (5 ± 1 g of body weight, equal males, and females were chosen for each group) were anesthetized by inhalation of isoflurane.…”

“…HIE resulting from oxygen deprivation and blood flow reduction to the brain is a common cause of brain damage [1]. The mechanisms involved in the brain damage include excitotoxicity, apoptosis, and glial overactivation [2]. Although the importance of microglial activation in hypoxia-induced neuroinflammation is well explored [3], the role of astrocyte activation in this process has attracted more attention.…”

TRPV1 translocated to astrocytic membrane to promote migration and inflammatory infiltration thus promotes epilepsy after hypoxic ischemia in immature brain

“…Neonatal hypoxia-ischemia brain damage (HIBD) remains a leading cause of severe neurological morbidity and mortality in neonates [1]. The mechanisms involved in brain damage include excitotoxicity, apoptosis, and glial overactivation [2]. Approximately 20% of newborns die in the postnatal period, 25% develop permanent neuropsychological sequelae such as epilepsy [3, 4], and 30% of children are unresponsive to conventional antiepileptic drugs due to resistance [5].…”

Hypoxic–ischemic injury causes functional and structural neurovascular degeneration in the juvenile mouse retina

“…This is a well-characterized model of neonatal HI and results in reproducible brain injury ipsilateral to the electrocauterized and transected left common carotid artery. We have successfully used this model to study the effect of HI on the neurovascular retina in mouse neonates 54 .…”

“…Although retinal ischemia and reperfusion in adult mice damage both the retinal neurons and the vasculature 53 , there is a lack of evidence to the outcome of ischemia in younger juvenile mice. We recently reported the attenuation of retinal neurovascular development in neonatal mice after exposure to hypoxic–ischemic (HI) conditions 54 . Here we determined the impact of HI on the retinal neurovascular integrity of 30-days old mice, equivalent to juvenile age in humans.…”