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    ABSTRACT: The serendipitous demonstration that the nonselective β-adrenergic receptor (β-AR) antagonist propranolol promotes the regression of infantile hemangiomas (IHs) aroused interest around the involvement of the β-adrenergic system in angiogenic processes. The efficacy of propranolol was related to the β2-AR blockade and the consequent inhibition of the production of vascular endothelial growth factor (VEGF), suggesting the hypothesis that propranolol could also be effective in treating retinopathy of prematurity (ROP), a retinal pathology characterized by VEGF-induced neoangiogenesis. Consequent to the encouraging animal studies, a pilot clinical trial showed that oral propranolol protects newborns from ROP progression, even though this treatment is not sufficiently safe. Further, animal studies clarified the role of β3-ARs in the development of ROP and, together with several preclinical studies demonstrating the key role of the β-adrenergic system in tumor progression, vascularization, and metastasis, prompted us to also investigate the participation of β3-ARs in tumor growth. The aim of this review is to gather the recent findings on the role of the β-adrenergic system in IHs, ROP, and cancer, highlighting the fact that these different pathologies, triggered by different pathogenic noxae, share common pathogenic mechanisms characterized by the presence of hypoxia-induced angiogenesis, which may be contrasted by targeting the β-adrenergic system. The mechanisms characterizing the pathogenesis of IHs, ROP, and cancer may also be active during the fetal–neonatal development, and a great contribution to the knowledge on the role of β-ARs in diseases characterized by chronic hypoxia may come from research focusing on the fetal and neonatal period.
    Medicinal Research Reviews 12/2014; DOI:10.1002/med.21336 · 8.13 Impact Factor
  • Investigative ophthalmology & visual science 10/2012; 53(11):7421-3. DOI:10.1167/iovs.12-10721 · 3.66 Impact Factor
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    ABSTRACT: The mouse model of oxygen-induced retinopathy (OIR) is a well-established model of retinopathy of prematurity (ROP), characterized by the abnormal formation of new blood vessels, which is similar to ROP. In this model, we have recently shown that subcutaneous (sc) administration of the non-selective beta-adrenergic receptor (β-AR) blocker propranolol ameliorates angiogenic processes in the retina when its effects are evaluated at postnatal day (PD) 17. In the present study, we investigated whether propranolol application as collyrium can promote the recovery of OIR. After propranolol administration on the eye, mice were first tested for retinal concentrations of propranolol as compared with those measured after sc or per os administration. Subsequently, we determined the effects of propranolol ophthalmic solutions, at the optimal dose for delivery, on VEGF, IGF-1, hypoxia-inducible factor (HIF)-1α, signal transducer and activator of transcription 3 (STAT3) and retinal neovascularization as assessed in both the superficial and the deep vascular plexuses. The results showed that 2% topical propranolol has an efficiency (in terms of final propranolol concentration in the retina) comparable to that of 20 mg/kg propranolol sc or per os and significantly higher than those observed with doses and administration routes that are currently used with children. Propranolol ophthalmic solutions reduced VEGF and IGF-1 up-regulation in response to hypoxia and drastically inhibited HIF-1α accumulation and STAT3 phosphorylation. As a result of its inhibitory effects on hypoxia-induced proangiogenic factors, propranolol significantly reduced retinal neovascularization in the superficial but not in the deep vascular plexus. An evaluation of retinal neovascularization at PD21 showed that propranolol was still effective in inhibiting OIR. These findings strengthen the hypothesis that β-AR blockade can efficiently counteract OIR and suggest that topical eye application of propranolol can represent an alternative delivery route to systemic administration thus avoiding the risk of associated complications and side effects that could make this drug unsafe in the ROP treatment.
    Experimental Eye Research 03/2013; 111. DOI:10.1016/j.exer.2013.03.013 · 3.02 Impact Factor