: Retinopathy of prematurity (ROP) is a disease that can cause blindness in very low birthweight infants. The incidence of ROP is closely correlated with the weight and the gestational age at birth. Despite current therapies, ROP continues to be a highly debilitating disease. Our advancing knowledge of the pathogenesis of ROP has encouraged investigations into new antivasculogenic therapies. The purpose of this article is to review the findings on the pathophysiological mechanisms that contribute to the transition between the first and second phases of ROP and to investigate new potential therapies. Oxygen has been well characterized for the key role that it plays in retinal neoangiogenesis. Low or high levels of pO₂regulate the normal or abnormal production of hypoxia‐inducible factor 1 and vascular endothelial growth factors (VEGF), which are the predominant regulators of retinal angiogenesis. Although low oxygen saturation appears to reduce the risk of severe ROP when carefully controlled within the first few weeks of life, the optimal level of saturation still remains uncertain. IGF‐1 and Epo are fundamentally required during both phases of ROP, as alterations in their protein levels can modulate disease progression. Therefore, rhIGF‐1 and rhEpo were tested for their abilities to prevent the loss of vasculature during the first phase of ROP, whereas anti‐VEGF drugs were tested during the second phase. At present, previous hypotheses concerning ROP should be amended with new pathogenetic theories. Studies on the role of genetic components, nitric oxide, adenosine, apelin and β‐adrenergic receptor have revealed new possibilities for the treatment of ROP. The genetic hypothesis that single‐nucleotide polymorphisms within the β‐ARs play an active role in the pathogenesis of ROP suggests the concept of disease prevention using β‐blockers. In conclusion, all factors that can mediate the progression from the avascular to the proliferative phase might have significant implications for the further understanding and treatment of ROP.

Oxygen-induced retinopathy (OIR) is a model for human retinopathy of prematurity (ROP). In OIR mice, this study determined whether blockade of β-adrenergic receptors (β-ARs) with propranolol influences retinal levels of proangiogenic factors, retinal vascularization, and blood-retinal barrier (BRB) breakdown. Propranolol was administered subcutaneously and picropodophyllin (PPP) intraperitoneally. Intravitreal injections of vascular endothelial growth factor (VEGF) were performed. Messengers of β-ARs, VEGF, its receptors, IGF-1 and IGF-1R were measured with quantitative RT-PCR. VEGF content was determined with ELISA. β-ARs, hypoxia-inducible factor (HIF)-1α, occludin, and albumin were measured with Western blot. Retinal localization of β3-ARs was determined by immunohistochemistry. Retinopathy was assessed by scoring fluorescein-perfused retinas, and plasma extravasation was visualized by Evans blue dye. Hypoxia did not influence β-AR expression, except that it increased β3-AR protein with dense β3-AR immunoreactivity localized to engorged retinal tufts. Hypoxia upregulated VEGF, IGF-1, their receptors, and HIF-1α. Propranolol dose-dependently reduced upregulated VEGF and decreased hypoxic levels of IGF-1 mRNA and HIF-1α. Blockade of IGF-1R activity with PPP did not influence propranolol's effects on VEGF. Retinal VEGF in normoxic mice or VEGF in brain, lungs, and heart of the OIR mice were unaffected by propranolol. Propranolol ameliorated the retinopathy score, restored occludin and albumin, and reduced hypoxia-induced plasma extravasation without influencing the vascular permeability induced by intravitreal VEGF. This is the first demonstration that β-AR blockade is protective against retinal angiogenesis and ameliorates BRB dysfunction in OIR. Although the relevance of these results to infant ROP is uncertain, the findings may help to establish potential pharmacologic targets based on β3-AR pharmacology.

Norepinephrine promotes tumor microenvironment reactivity through β3-adrenoreceptors during melanoma progression Norepinephrine promotes tumor microenvironment reactivity through β3-adrenoreceptors during melanoma progression

J. Neurochem. (2011) 10.1111/j.1471‐4159.2011.07530.x Oxygen‐induced retinopathy (OIR) is a model for human retinopathy of prematurity. In mice with OIR, beta‐adrenergic receptor (β‐AR) blockade with propranolol has been shown to ameliorate different aspects of retinal dysfunction in response to hypoxia. In the present study, we used the OIR model to investigate the role of distinct β‐ARs on retinal proangiogenic factors, pathogenic neovascularization and electroretinographic responses. Our results demonstrate that β₂‐AR blockade with ICI 118,551 decreases retinal levels of proangiogenic factors and reduces pathogenic neovascularization, whereas β₁‐ and β₃‐AR antagonists do not. Determination of retinal protein kinase A activity is indicative of the fact that β‐AR blockers are indeed effective at the receptor level. In addition, the specificity of ICI 118,551 on retinal angiogenesis has been demonstrated by the finding that in mouse retinal explants, β₂‐AR silencing prevents ICI 118,551 effects on hypoxia‐induced vascular endothelial growth factor accumulation. In OIR mice, ICI 118,551 is effective in increasing electroretinographic responses suggesting that activation of β₂‐ARs constitutes an important part of the retinal response to hypoxia. Lastly, immunohistochemical studies demonstrate that β₂‐ARs are localized to several retinal cells, particularly to Müller cells suggesting the possibility that β₂‐ARs play a role in regulating vascular endothelial growth factor production by these cells. The present results suggest that pathogenic angiogenesis, a key change in many hypoxic/ischemic vision‐threatening retinal diseases, depends at least in part on β₂‐AR activity and indicate that β₂‐AR blockade can be effective against retinal angiogenesis.