Limited hyperoxia-induced proliferative retinopathy: A model of persistent retinal vascular dysfunction, preretinal fibrosis and hyaloidal vascular reprogramming for retinal rescue

Abstract

Background Retinopathy of prematurity (ROP) remains the leading cause for blindness in children. Limited hyperoxia induced proliferative retinopathy (L-HIPR) was recently introduced as a potential animal model for ROP and persistent fetal vasculature; however, the detailed pathological changes remain unclear. Methods To model L-HIPR, we placed C57BL/6J mice in 65% oxygen from birth to post-natal day 7 (P7). We examined eyes at intervals between P12 and P30. Retinal morphometry, thickness, and preretinal fibrosis were quantified at different time points on histological sections stained with hematoxylin and eosin (H&E) and Masson Trichrome, respectively. Vascular development, angiogenesis, inflammation, and pericyte coverage were analyzed using immunohistochemistry staining in retinal flat mounts and cross sections. Results In L-HIPR, the hyaloidal vessels persisted until the latest time point in this study, P30 and began to invaginate the peripheral then central retina starting at P12. Central retinal distortion was noted beginning at P17, while the peripheral retina demonstrated a trend of thinning from P12 to P30. We found that L-HIPR was associated with delayed and abnormal retinal vascular development with subsequent retinal inflammation, pericyte loss and preretinal fibrosis. Conclusion Our study presents a detailed analysis of the L-HIPR animal model demonstrating vitreoretinal pathologic changes, preretinal fibrosis and persistent hyaloidal vessels into adulthood. Based on our findings, we suggest that the persistence and peculiar stepwise migration of the hyaloidal vessels into the retina may provide a potential rescue mechanism for inner retinal development that deserves further study.

Inflammation and aging: signaling pathways and intervention therapies

“…Ethanol induced premature senescence model 389,390 Growth arrest, increased SA-β-gal positive staining, overexpression of p21waf-1 and the subsequent inability to phosphorylate pRb, the presence of the common 4977-bp mitochondrial deletion, increased senescence-associated genes expression Hyperoxia induced model 391,392 Irreversible G1 cell cycle arrest, telomere shortening, increased protein degradation, increased lipofuscin/ceroid formation, and accumulation Oncogene-induced senescence (OIS) Mos-overexpression model 393 The growth arrest DNA damage, upregulation of p16INK4a, and increased SA-β-gal positive staining B-RAF V600E model 394,395 Cell cycle arrest, upregulation of p16INK4a, and increased SA-β-gal positive staining H-RAS G12V model 396,397 Upregulation of p16INK4a, low phosphorylated Rb, increased SAβ-gal positive staining…”

Early prediction of severe retinopathy of prematurity requiring laser treatment using physiological data

“… 2 , 12 , 24 – 26 The classic oxygen-induced retinopathy animal model describes the effect of hypoxia and hyperoxia in the pathophysiology of ROP with vaso-obliteration during hyperoxia exposure and vaso-proliferation during relative hypoxia, although further research is still needed for detailed understanding of pathological changes. 27 The ability of physiological and demographic data to predict severe ROP has been previously investigated by Sullivan et al 16 , although the pulse oximetry variables did not improve prediction in their analysis. Adding physiological data to the demographic data in our study did not significantly increase the performance of the models.…”

Pericyte in retinal vascular diseases: A multifunctional regulator and potential therapeutic target

“…For example, preretinal fibrosis often occurs at the end stage of proliferative retinopathy. 72,73 Resembling the healing process of wounds where fibrosis membranes form due to repeated bleeding of new vessels, neovascularization is frequently accompanied by fibrovascular membrane formation. Fibrosis membrane may impar vision by disrupting organized structure of the eye.…”

“…Fibrosis is a process that fibrous connective tissue develops in response to injury, sometimes referred to as “scar.” It protects injured tissue, but damages organ function subject to the position and area of the repairment. For example, preretinal fibrosis often occurs at the end stage of proliferative retinopathy 72,73 . Resembling the healing process of wounds where fibrosis membranes form due to repeated bleeding of new vessels, neovascularization is frequently accompanied by fibrovascular membrane formation.…”