Early Postnatal Hyperoxia in Mice Leads to Severe Persistent Vitreoretinopathy

McMenamin, Paul G.; Kenny, Rachel; Tahija, Sjakon G.; Lim, Jeremiah K. H.; Golborne, Cecilia Naranjo; Bouch, Sheena; Sozo, Foula; Bui, Bang V.

doi:10.1167/iovs.16-19928

Cited by 12 publications

(10 citation statements)

References 42 publications

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“…The reason for the discrepancy between the two studies is unclear, as key aspects of study design – including the O 2 percentage used – were similar. By contrast, our results are consistent with pathologies seen in young adult mice exposed to high oxygen from P0 to P7 ( McMenamin et al, 2016 ). Together, these findings suggest that initiation of hyperoxia earlier than the traditional OIR model ( Smith et al, 1994 ) can produce a different vascular phenotype, with the vitreoretinopathy and tractional detachments potentially mirroring some aspects of ROP ( Foos, 1987 ) that are not well modeled by OIR ( Gariano, 2010 ).…”

Section: Discussionsupporting

confidence: 91%

“…These include delays in peripheral vessel extension; persistent hyaloid vasculature; irregular and abnormally dense endothelial networks lacking regular capillary morphology; and vitreous hemorrhage. Because many of these vascular phenotypes resemble ROP (Eller et al, 1987;Foos, 1987;McMenamin et al, 2016), our results raise the possibility that astrocytes may have an important role in the pathobiology of ROP and related disorders.…”

Section: Discussionmentioning

confidence: 75%

“…For these reasons, we employed a protocol in which oxygen exposure starts at earlier stages. Unlike in standard OIR, a period of high oxygen at P0 can cause long-term retinal vascular pathology with features reminiscent of advanced ROP ( Lajko et al, 2016 ; McMenamin et al, 2016 ). Thus, mouse models featuring early oxygen elevation may have utility in understanding ROP pathogenesis and astrocyte involvement.…”

Section: Introductionmentioning

confidence: 99%

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Environmental oxygen regulates astrocyte proliferation to guide angiogenesis during retinal development

et al. 2021

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Angiogenesis in the developing mammalian retina requires patterning cues from astrocytes. Developmental disorders of retinal vasculature, such as retinopathy of prematurity (ROP), involve arrest or mispatterning of angiogenesis. Whether these vascular pathologies involve astrocyte dysfunction remains untested. Here, we demonstrate that the major risk factor for ROP – transient neonatal exposure to excess oxygen – disrupts formation of the angiogenic astrocyte template. Exposing newborn mice to elevated oxygen (75%) suppressed astrocyte proliferation, whereas return to room air (21% oxygen) at postnatal day 4 triggered extensive proliferation, massively increasing astrocyte numbers and disturbing their spatial patterning prior to the arrival of developing vasculature. Proliferation required astrocytic HIF2α and was also stimulated by direct hypoxia (10% oxygen), suggesting that astrocyte oxygen sensing regulates the number of astrocytes produced during development. Along with astrocyte defects, return to room air also caused vascular defects reminiscent of ROP. Strikingly, these vascular phenotypes were more severe in animals that had larger numbers of excess astrocytes. Together, our findings suggest that fluctuations in environmental oxygen dysregulate molecular pathways controlling astrocyte proliferation, thereby generating excess astrocytes that interfere with retinal angiogenesis.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 75%

Section: Introductionmentioning

confidence: 99%

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Environmental oxygen regulates astrocyte proliferation to guide angiogenesis during retinal development

et al. 2021

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“…Alternatively, switching between 50% and 10% oxygen every 12 hours can be applied from birth till P14 (Penn et al, 1994), resulting in different vascular phenotypes compared to the original OIR model. A more severe pathology that persists into adulthood is induced by exposing mice to hyperoxia at P0 for one or two weeks, resulting in retinal degeneration, scarring and detachment; culminating in a 50% reduction in retinal function and a persistent and hyperplastic hyaloid (Lajko et al, 2016;McMenamin et al, 2016).…”

Section: Mechanistic Insights From the Oir Modelmentioning

confidence: 99%

Retinal vasculature development in health and disease

Selvam

Kumar

Fruttiger

2018

Progress in Retinal and Eye Research

253

252

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Development of the retinal vasculature is based on highly coordinated signalling between different cell types of the retina, integrating internal metabolic requirements with external influences such as the supply of oxygen and nutrients. The developing mouse retinal vasculature is a useful model system to study these interactions because it is experimentally accessible for intra ocular injections and genetic manipulations, can be easily imaged and develops in a similar fashion to that of humans. Research using this model has provided insights about general principles of angiogenesis as well as pathologies that affect the developing retinal vasculature. In this review, we discuss recent advances in our understanding of the molecular and cellular mechanisms that govern the interactions between neurons, glial and vascular cells in the developing retina. This includes a review of mechanisms that shape the retinal vasculature, such as sprouting angiogenesis, vascular network remodelling and vessel maturation. We also explore how the disruption of these processes in mice can lead to pathology - such as oxygen induced retinopathy - and how this translates to human retinopathy of prematurity.

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“…Chronic exposure to hyperoxia causes oxidative stress and contributes to the pathogenesis of injury in the preterm as well as full-term brain, with a dramatic deterioration of brain function in later life [7]. Neonatal hyperoxia causes severe vitreoretinal pathologic changes that persist into adulthood [8]. Thus, it is important to clarify the adverse impact of neonatal hyperoxia upon nephrogenesis.…”

Section: Introductionmentioning

confidence: 99%

Proximal Tubular Development Is Impaired with Downregulation of MAPK/ERK Signaling, HIF-1α, and Catalase by Hyperoxia Exposure in Neonatal Rats

You

2019

Oxidative Medicine and Cellular Longevity

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Supplemental oxygen therapy (hyperoxia) is a widely used treatment for alveolar hypoxia in preterm infants. Despite being closely monitored, hyperoxia exposure is believed to undermine neonatal nephrogenesis and renal function caused by elevated oxidative stress. Previous studies have mostly focused on the hyperoxia-induced impairment of glomerular development, while the long-term impact of neonatal hyperoxia on tubular development and the regulatory component involved in this process remain to be clarified. Here, we examined tubular histology and apoptosis, along with the expression profile of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling, hypoxia-inducible factor 1α (HIF-1α), and catalase, following hyperoxia exposure in neonatal rats. Hematoxylin and eosin (H&E) staining revealed the early disappearance of the nephrogenic zone, as well as dilated lumens and reduced epithelial cells, of mature proximal tubules following neonatal hyperoxia. A robust increase in tubular cell apoptosis caused by neonatal hyperoxia was found using a TUNEL assay. Moreover, neonatal hyperoxia altered renal MAPK/ERK signaling activity and downregulated the expression of HIF-1α and catalase in the proximal tubules throughout nephrogenesis from S-shaped bodies to mature proximal tubules. Cell apoptosis in the proximal tubules was positively correlated with HIF-1α expression on the 14th postnatal day. Our data indicates that proximal tubular development is impaired by neonatal hyperoxia, which is accompanied by altered MAPK/ERK signaling as well as downregulated HIF-1α and catalase. Therapeutic management that targets MAPK/ERK signaling, HIF-1α, or catalase may serve as a protective agent against hyperoxia-induced oxidative damage to neonatal proximal tubules.

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Early Postnatal Hyperoxia in Mice Leads to Severe Persistent Vitreoretinopathy

Abstract: This animal model displays a mixture of vitreoretinal pathologic changes that persist into adulthood. The model may prove valuable in experimental investigations of therapeutic approaches to blinding conditions caused by vitreous and retinal abnormalities.

Cited by 12 publications

References 42 publications

Environmental oxygen regulates astrocyte proliferation to guide angiogenesis during retinal development

Environmental oxygen regulates astrocyte proliferation to guide angiogenesis during retinal development

Retinal vasculature development in health and disease

Proximal Tubular Development Is Impaired with Downregulation of MAPK/ERK Signaling, HIF-1α, and Catalase by Hyperoxia Exposure in Neonatal Rats

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