Genetic Inactivation of the Adenosine A_2AReceptor Attenuates Pathologic but Not Developmental Angiogenesis in the Mouse Retina

Abstract

These findings provide the first evidence that A(2A)R is critical for the development of OIR and suggest a novel therapeutic approach of A(2A)R inactivation for ROP by selectively targeting pathologic but not developmental angiogenesis in the retina.

Adenosine A1Receptors Selectively Modulate Oxygen-Induced Retinopathy at the Hyperoxic and Hypoxic Phases by Distinct Cellular Mechanisms

“…In support of this view, we have recently demonstrated that genetic inactivation of the A 2A R attenuated hypoxia-induced pathologic angiogenesis without affecting normal postnatal retinal vascularization. 15 Therapeutic potential of adenosine receptor-based therapy for ROP is supported by the ability of adenosine receptors to modulate inflammation, neuroprotection, and angiogenesis in retina through activation of four G-protein-coupled receptors, namely, A 1 , A 2A , A 2B , and A 3 , all of which have been detected in retina. 16,17 Increased adenosine acting at A 2A Rs suppresses neuroinflammation and protects against diabetic retinopathy (DR) 18 and traumatic optic neuropathy, 19 through control of retinal microglial function and production of proinflammatory cytokines 20,21 ; studies with genetic inactivation of the A 2A R, 15 with A 2B R antagonists [22][23][24] and with ribozyme approach to inactivating A 2B Rs, demonstrate that adenosine acting at the A 2A and A 2B receptors promotes pathologic angiogenesis in retina through modulating VEGF level.…”

“…15 Therapeutic potential of adenosine receptor-based therapy for ROP is supported by the ability of adenosine receptors to modulate inflammation, neuroprotection, and angiogenesis in retina through activation of four G-protein-coupled receptors, namely, A 1 , A 2A , A 2B , and A 3 , all of which have been detected in retina. 16,17 Increased adenosine acting at A 2A Rs suppresses neuroinflammation and protects against diabetic retinopathy (DR) 18 and traumatic optic neuropathy, 19 through control of retinal microglial function and production of proinflammatory cytokines 20,21 ; studies with genetic inactivation of the A 2A R, 15 with A 2B R antagonists [22][23][24] and with ribozyme approach to inactivating A 2B Rs, demonstrate that adenosine acting at the A 2A and A 2B receptors promotes pathologic angiogenesis in retina through modulating VEGF level. 25 The translational potential of adenosine receptor-based therapy for controlling proliferative retinopathy is substantiated by a clinical potential, since a recent large clinical trial of 2006 infants has demonstrated that treatment with caffeine, a nonselective adenosine receptor antagonist, reduces ROP-related problems after 2-year follow-up, 26 and by genetic identification of the variants of the human A 2A R gene that are associated with reduced risk of developing DR in a prospective study.…”

“…25 The translational potential of adenosine receptor-based therapy for controlling proliferative retinopathy is substantiated by a clinical potential, since a recent large clinical trial of 2006 infants has demonstrated that treatment with caffeine, a nonselective adenosine receptor antagonist, reduces ROP-related problems after 2-year follow-up, 26 and by genetic identification of the variants of the human A 2A R gene that are associated with reduced risk of developing DR in a prospective study. 27 Several studies of adenosine receptor control of retinal vascularization have focused on the A 2A R effect, 11,15,18 with some on the A 2B receptor. 25 Adenosine A 1 receptor (A 1 R) mRNA and ligand binding are detected in developing retina.…”

Pathomorphological Features of the Development of Experimental Retinopathy of Prematurity

“…Подтверждением этому служит обнару- Полученные на нашей крысиной модели РН «60/15» результаты согласуются с дан-ными литературы. Так, группой ученых на мышиной модели заболевания было показа-но, что при развитии ретинопатии на сроке, соответствующем пику неоваскуляризации, в препаратах сетчатки мышат определя-ются пролиферирующие ядра клеток, ло-кализующихся с витреальной стороны от ВПМ сетчатки, в которых при иммуноги-стохимическом исследовании выявлялась повышенная экспрессия PCNA [9]. В ряде других исследований на крысиной модели РН «50/10» в препаратах сетчатки на 18-е сутки, которые также представляют собой пик неоваскуляризации в данной модели, определялись новообразованные сосуды на поверхности сетчатки в периферических отделах [5].…”

Selection Strategy of In Vivo Models for Ophthalmic Drug Development in Diabetic Retinopathy

“…Different studies also demonstrated that new blood vessel formation can also be reduced by inhibition of expression or activity of mediators involved in other angiogenesis related signaling pathways such as Epo [193], NO [194,195], apelin [196], adenosine [197,198] and fatty acid binding protein 4 (FABP4) [199]. Importantly, recent studies have demonstrated that angiogenesis can be controlled by the adrenergic system through its regulation of pro-angiogenic factors [200,201].…”