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    • br Aberrantly enhanced adenosine signaling in retina of oxyg

    2024-03-08


    Aberrantly enhanced adenosine signaling in retina of oxygen-induced retinopathy Current therapeutic development of ROP focuses on directly targeting VEGF and HIF-1α signaling pathway (Cavallaro et al., 2014, Penn et al., 2008, Mintz-Hittner et al., 2011, Hartnett and Penn, 2012). However, cellular responses to hypoxia are characterized by robust increases in extracellular adenosine production (up to 100 folds) and signaling events through the markedly induced adenosine receptors (up to 50 folds) locally (Chen et al., 2013). Adenosine is a naturally occurring nucleoside that is distributed ubiquitously throughout the body as a metabolic intermediary and neuromodulator in the brain. Extracellular adenosine acts through multiple G-protein-coupled receptors (i.e. A1, A2A, A2B and A3) (Fredholm et al., 2001) to exert control over blood vessel growth in various tissues, including retina, both under normal and pathological conditions (Adair et al., 2005, Patz, 1980). All four adenosine receptor subtypes have been detected in retina (Cui et al., 2010, Brito et al., 2012). Hypoxia triggers the surge in extracellular adenosine level as a result of transcriptional induction of CD73 and equivalent nucleotide transporter 1 as well as suppression of adenosine kinase, thereby elevating the capacity of local tissues for extracellular adenosine production (Lutty and McLeod, 2003, Elsherbiny et al., 2013a). Indeed, pioneering studies by Lutty and colleagues showed that 5′ nucleotidase and adenosine were reduced during the hyperoxia phase but markedly increased in the hypoxic retina using a neonatal canine model of OIR, (Lutty and McLeod, 2003, Takagi et al., 1996, Taomoto et al., 2000, Lutty et al., 2000). Adenosine accumulating locally during hypoxia permits the local control of retinal vessel growth (Lutty and McLeod, 2003). Pathological conditions such as OIR are also accompanied by the increases of local inflammatory cytokines such as interleukin-1β (IL-1β) and tumor necrosis factor–α (TNF-α), which lead to a delayed (∼24 h), marked and sustained increases in adenosine receptor (particularly the A2AR and the A2BR) expression in tissues and inflammatory Batimastat (Frick et al., 2009, Schingnitz et al., 2010, Linden, 2011). In OIR models of ROP, the expression of A2AR was suppressed during the hyperoxic phase, but markedly increased in hypoxic retina, supporting the possible involvement of adenosine-A2AR signaling in retinal pathological angiogenesis (Lutty and McLeod, 2003, Takagi et al., 1996, Taomoto et al., 2000, Lutty et al., 2000) (see Fig. 1A). Locally increased adenosine levels and adenosine receptor signaling might represent a local “find-me” signal and serve as a unique “purinergic chemotaxis” for a local resolution to pathological conditions (as revealed by genetic KO studies) (Chen et al., 2013). Thus, the surge of adenosine level and the induction of adenosine receptors in the hypoxic phase of OIR (Lutty and McLeod, 2003) may constitute a negative feedback and defense mechanism countering such pro-angiogenic statues triggered by hypoxia and HIF-1α-mediated expression of VEGF in retina. Increased adenosine-adenosine receptor signaling in hypoxic retina also offers an opportunity of targeting pathological angiogenesis of ROP with minimal effects on normal retinal vascular development. Consequently, we propose that A2AR activity in the retina has the potential to modulate normal retinal vascularization and/or pathological angiogenesis.
    The role of adenosine receptors in development of ROP Therapeutic potential of adenosine receptors-based therapy for ROP is supported by the ability of adenosine subtype receptors to modulate inflammation, neuroprotection and angiogenesis in retina. In particular, numerous studies support the role of adenosine receptors in modulating the angiogenic effects in various cell types and tissues (Adair, 2005), including cardiomyocyte (Deussen, 2000), skeletal muscle fiber (Lynge et al., 2001), skin (Feoktistov et al., 2009, Valls et al., 2009) and retina (Adair, 2005, Grant et al., 2001). The translational potential of adenosine receptor-based therapy for controlling proliferative retinopathy is substantiated by clinical evidence that clinical treatment of apnea of prematurity with caffeine (a non-selective adenosine receptor antagonist) reduced ROP related problems (Schmidt et al., 2007) (see below), and by genetic identification of the variants of the human A2AR gene that are associated with reduced risk of developing diabetic retinopathy (Charles et al., 2011).