Adenosine in Retinal Vasculogenesis and Angiogenesis in Oxygen-Induced Retinopathy

Abstract

Adenosine is a ubiquitous molecule produced predominantly by catabolism of adenosine triphosphate. Levels of this nucleoside increase dramatically with ischemia and elevated tissue activity. Adenosine induces angiogenesis in tumors and wound healing and upregulates VEGF production in several cell types, including endothelial cells. The source of adenosine in most tissues appears to be the ectoenzyme 5' nucleotidase, which is hypoxia inducible. 5' nucleotidase expression is prominent during retinal vascular development in the innermost processes of Muller cells, and levels of its product, adenosine, are high in inner retina during retinal vascular development in postnatal dog. One of the adenosine receptors, A(2A), is present on angioblasts and on endothelial cells of formed blood vessels during canine retinal vascular development. These observations suggest that adenosine is important in retinal vascular development. Oxygen-induced retinopathy (OIR) is a model for human retinopathy of prematurity (ROP). OIR is induced by exposure of the developing retina to high oxygen. Vascular development is halted, and over 60% of the retinal vasculature is lost during this stage, which is called vaso-obliteration. Expression of 5' nucleotidase is dramatically reduced during vaso-obliteration, resulting in a sharp decline in adenosine. When animals are returned to room air, the retina is hypoxic because of the lack of blood vessels and increased oxygen consumption due to neuronal development. At this time, the vasoproliferative stage of OIR begins, and 5' nucleotidase activity and adenosine levels become elevated well beyond normal. A(2A)-positive endothelial cell proliferation is also elevated compared to control animals. Florid preretinal neovascularization occurs and is characterized by high levels of adenosine and A(2A) receptors. Therefore, adenosine and its A(2A) receptor appear to be important in canine OIR. This has also been demonstrated in the mouse model of OIR. Systemically administered antagonists of the adenosine A(2B) receptor significantly reduced retinal neovascularization in mice,(1) as did cleavage of A(2B) by a ribozyme.(2) These studies suggest that adenosine and its receptors are important in retinal vascular development and may be a therapeutic target in OIR.