Adenosine Receptor 2a-Mediated Endothelial Glycolysis Critically Contributes To Pathological Angiogenesis Of Retina

Pathological proliferative retinopathy is the most common cause of blindness in patients of all ages worldwide. Investigation of the molecular mechanisms underlying pathological retina neovascularization is critical to the development of new therapeutic strategies. In the current study, we investigated the effect of macrophage or endothelial cell adenosine receptor 2A (A 2A R) deletion in pathological retinal vascular growth, and further explored the potential mechanism. Our results showed that: (1) A 2A R expression was localized to retinal vessels and was markedly induced in pathological neovascularization tufts in a mouse model of oxygen-induced proliferative retinopathy (OIR) (Figure A); (2) endothelial cell, but not macrophage, -specific A 2A R deletion significantly decreased pathological neovascularization in the mouse OIR model (Figure B);. The levels of glycolytic enzymes, angiogenic factors and lactate secretion were markedly reduced in retina of endothelial cell-specific A 2A R knockout mice; (3) in human retinal microvascular endothelial cells (HRMECs), hypoxia markedly induced the expression of A 2A R, but not A 1 R, A 2B R and A 3 R, by activating HIF-2α. Deletion or blockade of A 2A R by small interfering RNA (siRNA) or antagonist ZM241385 decreased hypoxia or adenosine-induced glycolytic enzyme expression, lactate secretion and cell proliferation via suppression of the cAMP/PKA/CREB/HIF-1α pathway; (4) blockade of glycolysis by 3PO or 2-DG abolished the adenosine-induced HRMEC proliferation under hypoxic conditions. Taken together, we have demonstrated a critical role of endothelial cell A 2A R in promoting pathological vascular development and revealed a novel glycolysis-driven mechanism for endothelial cell A 2A R-mediated pathological angiogenesis in proliferative retinopathy. Thus, A 2A R is a promising therapeutic target in the treatment of proliferative retinopathy.