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Tianwei (Ellen) Zhou, Tang Zhu, Samy Omri, Raphaël Rouget, Houda Tahiri, Jose Carlos Rivera, Stanley Nattel, Sylvain Chemtob; Oxidative stress suppresses choroidal revascularization via a Tp53-dependent pathway in oxygen-induced retinopathy (OIR). Invest. Ophthalmol. Vis. Sci. 2017;58(8):4071.
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© ARVO (1962-2015); The Authors (2016-present)
Retinopathy of prematurity (ROP) is a serious complication in premature infants. Although the inner retina is immediately impaired in ROP, photoreceptor malfunction, retinal pigment epithelium (RPE) injury and subretinal hypoxia are also observed. These damages appear to result from a sustained thinning of choroid, the major retinal blood supple. Reparative angiogenesis following initial endothelial injury is highly desirable as prolonged ischemia-hypoxia can cause irreversible tissue damage. Paradoxically, in oxygen-induced retinopathy (OIR), choroidal involution is persistent despite severe subretinal hypoxia (which would normally trigger revascularization).High O2 tension contributes to ROP; and oxidative stress is known to suppress vascular repair. In OIR, tumour suppressor p53 (Tp53, a key regulator of angiogenesis) is activated by retinal oxidative stress. Here, we examined the molecular mechanism through which Tp53 suppresses choroidal revascularization.
The OIR model was induced by exposing Sprague-Dawley rat pups to cycling O2 (10%/50%) from postnatal day (P)1 to P14. Angiogenic capacity was examined via ex-vivo choroidal explant assay. Small interference RNA (siRNA) targeting p53 was designed and introduced to rats through subretinal injection. Protein and mRNA levels were assessed via western blot and qPCR.
Starting on P3 of OIR, NADPH oxidases, the major producers of reactive oxygen species, were significantly upregulated in RPE and choroid, whereas superoxide dismutases 1 and 2 (antioxidant defense) were insufficient. Accordingly, Tp53 was promptly upregulated and activated. Transcriptomic profiling, qPCR and western blot analyses confirmed curtailed insulin-like growth factor 1 receptor (IGF1R) level. Interestingly, abrogation of Tp53 via siRNA rescued the expression of IGF1R, insulin-like growth factor 1 (IGF1), and vascular endothelial growth factor a (VEGFa), in addition to ameliorating choroidal integrity.
Collectively, our study revealed, for the first time, the central role of Tp53 in orchestrating an antiagiogenic milieu at RPE/choroid by reducing IGF1R, resulting in a lack of choroidal revascularization despite apparent ischemia-hypoxia. Targeting the Tp53-IGF1R axis represents a sensible therapeutic avenue to promote vascular restoration in retinopathies (e.g. geographic atrophy) associated with choroidal degeneration.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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