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  • Control of retinal vascularization during development

    2024-02-06

    Control of retinal vascularization during development and OIR likely involves close interactions among endothelial cells, neurons and glial bcr-abl inhibitor (microglial and astrocytes) (see Fig. 2). In particular, the interaction between endothelial tip cells and astrocytes plays a critical role in developmental blood vessel formation and physiological revascularization (Wood and Martin, 2002). Astrocytes play a significant role in angiogenesis in response to hypoxia through their high expression of VEGF (Dorrell and Friedlander, 2006). Studies in OIR models showed that the density of astrocytes in the retina decreases during hyperoxia and then increases following hypoxia (Chan-Ling et al., 1992, Downie et al., 2008), and that restoring retinal astrocytes reduces vascular pathology associated with OIR (Weidemann et al., ; Dorrell et al.,). Neuronal mechanisms in retina may also contribute to retinal vascularization of ROP, particularly during the hyperoxic phase. In the vaso-obliteration phase, hyperoxia induces apoptosis of ganglia cells and developing endothelial cells and inhibits endothelial cell proliferation and migration, resulting in vaso-obliteration (Aiello et al., 1994, Alon et al., 1995). Activation of retinal A1Rs has been shown to inhibit Ca++ channels in retinal ganglion cells of mini-slices (Sun et al., 2002, Santos et al., 2000), protect NMDA-induced cell death in cultured retinal neurons (Oku et al., 2004), and mediate the interleukin-6 effect on the survival of cultured retinal ganglion cells (Perigolo-Vicente et al., 2013). Consistent with the A1R-mediated neuroprotective effect, early studies indicated that cytotoxicity and cell death were generally more pronounced in neurons and astrocytes derived from A1R KO mice (Bjorklund et al., 2008, Dunwiddie and Masino, 2001, Johansson et al., 2001). In addition, in parallel with the avascular area, A2AR KO attenuates TUNEL-positive cells in the inner nuclear layer of retina (unpublished data), suggesting that A1R and A2AR KO probably protect against hyperoxia-induced damage to developing retinal vessels by modulating neuronal apoptosis.
    Caffeine and ROP The translational potential of adenosine receptor-based therapy for controlling proliferative retinopathy is substantiated by its clinical potentials of caffeine treatment in reducing ROP related problems in premature infants. In a recent large prospective clinical phase III trial with caffeine treatment for apnea in premature infants, caffeine treatment apparently reduces the severity of ROP as compared to that of the control in a two-year follow-up observation (Schmidt et al., 2007). The therapeutic potential of caffeine for ROP is further supported by the ability of caffeine to control angiogenic factors HIF-1α and VEGF (Merighi et al., 2007, Ryzhov et al., 2007), angiogenesis (Ryzhov et al., 2007, Hsu et al., 2015) and apoptosis of endothelium cells (Li et al., 2013) and other vascular actions (Echeverri et al., 2010). This raises an exciting possibility that caffeine, the ubiquitous trimethylxanthine that is widely used in premature infants with apnea of prematurity (Abdel-Hady et al., 2015) may protect against pathological neovascularization in ROP. The protection against ROP by caffeine is in general agreement with the finding that caffeine treatment reduced the vulnerability of the immature brain to hypoxic ischemia (Bona et al., 1995), reduced the effects of NMDA on e.g. seizure susceptibility (Georgiev et al., 1993) in neonates. Moreover, our recent study demonstrate that caffeine treatment at the concentration of 0.1 g/L −1.0 g/L from P0-P17 reduced nonvascular areas by 31.28–53.78%, respectively, and also reduced neovascular nuclei counting (Zhou et al., 2015). Furthermore, we also found that repeated treatment of the A2AR antagonist KW6002 at P7-P14 reduced avascular areas as well as neovascularization at P17 as revealed by isolectin B4-immunostaining, consistent with notion that adenosine receptors are the main pharmacological targets of caffeine's actions (Zhou et al., 2015). Lastly, chronic treatment with caffeine or KW6002 did not affect normal retinal neovascularization during postnatal development (Zhou et al., 2015). These findings provide the biological basis for the clinical finding that the use of caffeine in treatment of apnea in premature infants is associated with reduced ROP. Collectively, these findings support the novel caffeine- and adenosine receptor-based pharmacologic treatment for ROP. Further studies to identify the molecular targets, the cellular mechanism and effective therapeutic window underlying the protective effects of caffeine are needed to optimize caffeine treatment regime to target specific molecular pathways to achieve maximize prophylactic benefits for ROP while maintaining their impressive safety profiles.