Sildenafil Attenuates Vaso-Obliteration and Neovascularization in a Mouse Model of Retinopathy of Prematurity

Fawzi, Amani A.; Chou, Jonathan; Kim, Gina A.; Rollins, Stuart D.; Taylor, Joann M.; Farrow, Kathryn N.

doi:10.1167/iovs.13-13207

Cited by 10 publications

(10 citation statements)

References 62 publications

(72 reference statements)

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“…It is difficult, however, to separate the impact of sildenafil from concurrent neonatal risk factors for retinopathy of prematurity (e.g., significant O 2 exposure, PDA ligation) in reported cases. A few small human studies suggest no increased risk (96,97) and O 2 -mediated neovascularization is reduced by sildenafil administration in a mouse model (98). In sick preterms with concurrent cardiovascular instability, the nonspecific vasodilator effects on systemic blood pressure also merit consideration.…”

Section: Approach To Respiratory Supportmentioning

confidence: 99%

Controversies in the identification and management of acute pulmonary hypertension in preterm neonates

Giesinger

Odame

et al. 2017

Pediatr Res

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It is increasingly recognized that the abnormal physiologic consequences of pulmonary hypertension (PH) may contribute to poor cardiopulmonary health in premature babies. Conflicting literature has led to clinical uncertainty, pathological misinterpretation, and variability in treatment approaches among practitioners. There are several disorders with overlapping and interrelated presentations, and other disorders with a similar clinical phenotype but diverse pathophysiological contributors. In this review, we provide a diagnostic approach for acute hypoxemic respiratory failure in the preterm neonate, outline the pathophysiological conditions that may present as acute PH, and discuss the implications of high pulmonary vascular resistance (PVR) on the cardiovascular system. Although PVR and respiratory management are highly interrelated, there may be a population of preterm neonates in whom inhaled nitric oxide may improve illness severity and may relate to outcomes. A management approach based on physiology that considers common clinical conundrums is provided. A more comprehensive understanding of the physiology may help in informed decision-making in clinical situations where conclusive scientific evidence is lacking. Regardless, high-quality research is required, and appropriate definition of the target population is paramount. A thoughtful approach to cardiovascular therapy may also provide an avenue to improve neurodevelopmental outcomes while awaiting more clear answers.

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Section: Approach To Respiratory Supportmentioning

confidence: 99%

Controversies in the identification and management of acute pulmonary hypertension in preterm neonates

Giesinger

Odame

et al. 2017

Pediatr Res

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“…Another possible vascular effect of sildenafil is through the modulation of retinal angiogenesis. 47 Fawzi et al 31 reported that sildenafil administration in a neonatal mouse model of oxygen-induced retinopathy prevented the hyperoxia-induced retinal vaso-obliteration through hypoxia-inducible factor 1-a (HIF-a) stabilization, which in turn prevented the retinal neovascularization known to take place when the pups are returned to normoxia.…”

Section: Discussionmentioning

confidence: 99%

“…We administered sildenafil by oral route instead of the intraperitoneal or subcutaneous route described in most of the previous animal experiments, 14,16,17,31,46 because oral sildenafil is the most commonly used route with human newborns. It is safe to assume that oral sildenafil reaches the retina, as it has been demonstrated to transiently affect the ERG in healthy human subjects 1 hour after intake.…”

Section: Discussionmentioning

confidence: 99%

“…20 In fact, one study suggested that vaso-obliteration and neovascularization, which are the hallmarks of retinopathy of prematurity, were decreased after sildenafil administration in a mouse model of retinopathy of prematurity. 31 Thus, we hypothesized that sildenafil may be a therapeutic candidate to treat retinal injury induced by neonatal HI at termequivalent age. In this study, we investigated the effects of neonatal HI on retinal function and structure and whether different doses of sildenafil could alleviate the retinal anomalies induced by neonatal HI in a rat model of term neonatal encephalopathy.…”

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confidence: 99%

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Sildenafil Improves Functional and Structural Outcome of Retinal Injury Following Term Neonatal Hypoxia-Ischemia

Jung

Johnstone

Khoja

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. The purpose of this study was to investigate the effects of sildenafil on retinal injury following neonatal hypoxia-ischemia (HI) at term-equivalent age in rat pups.METHODS. Hypoxia-ischemia was induced in male Long-Evans rat pups at postnatal day 10 (P10) by a left common carotid ligation followed by a 2-hour exposure to 8% oxygen. Shamoperated rats served as the control group. Both groups were administered vehicle or 2, 10, or 50 mg/kg sildenafil, twice daily for 7 consecutive days. Retinal function was assessed by flash electroretinograms (ERGs) at P29, and retinal structure was assessed by retinal histology at P30.RESULTS. Hypoxia-ischemia caused significant functional (i.e., attenuation of the ERG a-wave and b-wave amplitudes and photopic negative response) and structural (i.e., thinning of the total retina, especially the inner retinal layers) retinal damage in the left eyes (i.e., ipsilateral to the carotid ligation). Treatment with the different doses of sildenafil led to a dose-dependent increase in the amplitudes of the ERG a-and b-waves and of the photopic negative response in HI animals, with higher doses associated with greater effect sizes. Similarly, a dose response was observed in terms of improvements in the retinal layer thicknesses.CONCLUSIONS. Hypoxia-ischemia at term-equivalent age induced functional and structural damage mainly to the inner retina. Treatment with sildenafil provided a dose-dependent recovery of retinal function and structure.

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“…Retinas were processed as described previously [34]. Briefly, immediately after enucleation, retinas were dissected and lysed in 1X Mg2+ lysis buffer (EMD Millipore, Billerica, MA) with a protease inhibitor cocktail (Sigma Aldrich, St. Louis, MO) and a phosphatase inhibitor cocktail (EMD Millipore).…”

Section: Methodsmentioning

confidence: 99%

Hyperoxia-Induced Proliferative Retinopathy: Early Interruption of Retinal Vascular Development with Severe and Irreversible Neurovascular Disruption

Lajko¹,

Cardona²,

Taylor³

et al. 2016

PLoS ONE

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Bronchopulmonary dysplasia (BPD) is a major cause of neonatal morbidity in premature infants, occurring as a result of arrested lung development combined with multiple postnatal insults. Infants with BPD exposed to supplemental oxygen are at risk of retinopathy of prematurity as well. Thus, we studied the effects of hyperoxia on the retinal vasculature in a murine model of BPD. The retinal phenotype of this model, which we termed hyperoxia-induced proliferative retinopathy (HIPR), shows severe disruption of retinal vasculature and loss of vascular patterning, disorganized intra-retinal angiogenesis, inflammation and retinal detachment. Neonatal mice were subjected to 75% oxygen exposure from postnatal day (P)0 to P14 to model BPD, then allowed to recover in room air for 1 (P15), 7 (P21), or 14 days (P28). We quantified retinal thickness, protein levels of HIF-1α, NOX2, and VEGF, and examined the cellular locations of these proteins by immunohistochemistry. We examined the retinal blood vessel integrity and inflammatory markers, including macrophages (F4/80) and lymphocytes (CD45R). Compared to controls, normal retinal vascular development was severely disrupted and replaced by a disorganized sheet of intra-retinal angiogenesis in the HIPR mice. At all time-points, HIPR showed persistent hyaloidal vasculature and a significantly thinner central retina compared to controls. HIF-1α protein levels were increased at P15, while VEGF levels continued to increase until P21. Intra-retinal fibrinogen was observed at P21 followed by sub-retinal deposition in at P28. Inflammatory lymphocytes and macrophages were observed at P21 and P28, respectively. This model presents a severe phenotype of disrupted retinal vascular development, intra-retinal angiogenesis inflammation and retinal detachment.

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Sildenafil Attenuates Vaso-Obliteration and Neovascularization in a Mouse Model of Retinopathy of Prematurity

Cited by 10 publications

References 62 publications

Controversies in the identification and management of acute pulmonary hypertension in preterm neonates

Controversies in the identification and management of acute pulmonary hypertension in preterm neonates

Sildenafil Improves Functional and Structural Outcome of Retinal Injury Following Term Neonatal Hypoxia-Ischemia

Hyperoxia-Induced Proliferative Retinopathy: Early Interruption of Retinal Vascular Development with Severe and Irreversible Neurovascular Disruption

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