Infantile hemangiomas, retinopathy of prematurity and cancer: a common pathogenetic role of the beta-adrenergic system

The serendipitous demonstration that the non-selective β-adrenergic receptor (β-AR) antagonist propranolol promotes the regression of infantile hemangiomas (IHs), the most common vascular tumor of infancy, aroused an interest around the involvement of the β-adrenergic system in angiogenic processes in humans. Several studies provided evidence that the efficacy of propranolol was related to the blockade of the β2-AR and the consequent inhibition of the production of vascular endothelial growth factor (VEGF). These findings suggested the hypothesis that β2-AR blockade could also be effective in treating retinopathy of prematurity (ROP), a retinal pathology characterized by VEGF-induced retinal neo-angiogenesis. Consequent to the encouraging results obtained in mice with oxygen-induced retinopathy, a worldwide used animal model of ROP, a pilot clinical trial showed that oral propranolol protects newborns from ROP progression, even though this treatment is not sufficiently safe. Then, further animal studies were aimed at clarifying the role of β3-ARs in the development of ROP and in mechanisms related to angiogenic processes. The results of these investigations, 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 the present 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, although 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. As a conclusion, we propose that the mechanisms characterizing the pathogenesis of IHs, ROP and cancer may also be active during the fetal and 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.