Recent therapeutic approaches against retinopathy of prematurity (ROP) have focused on the mechanisms leading to neoangiogenesis. In a typical mouse models of oxygen-induced retinopathy (OIR), hypoxia induces abnormal formation of new blood vessels which is assimilable to ROP and involves up-regulation of the vascular endothelial growth factor (VEGF). There is some evidence that angiogenesis can be controlled by the adrenergic system through its regulation of proangiogenic factors. We investigated whether beta-adrenoreceptor (b-AR) blockade reduces the hypoxia-induced VEGF up-regulation in the retina of OIR mice. Using Real Time PCR, Western blot and ELISA, we found that levels of VEGF mRNA and protein were dose-dependently reduced by the b-AR non-selective blocker propranolol. VEGF levels were unaffected by either atenolol (b1-AR blocker) or SR59230A (b3-AR blocker), whereas they were significantly reduced by ICI 118,551 (b2-AR blocker). b-AR mRNA was not influenced by hypoxia. At the protein level, hypoxia did not influence either b1- or b2-ARs but significantly increased b3-ARs. By immunohistochemistry, we observed that b3-AR was overexpressed at the level of engorged retinal tufts in the inner capillary network of the hypoxic retina. In conclusion, b3-ARs although up-regulated by hypoxia are not involved in VEGF regulation, whereas b2-AR blockade mediates the propranolol-induced down-regulation of VEGF. This finding suggests a crosstalk between b3- and b2-ARs that might render the hypoxic retina susceptible to antiangiogenic effects of b2-AR blockade. Our data are intriguing in light of the possible therapeutic use of b-AR blockers to counteract retinal neovascularization in ROP.