Infantile Hemangiomas, Retinopathy of Prematurity and Cancer: A Common Pathogenetic Role of the β‐Adrenergic System

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.

Early and Late Histological and Ultrastructural Findings in Resected Infantile Capillary Hemangiomas Following Treatment with Topical Beta-Blocker Timolol Maleate 0.5%

“…This would be consistent with the expression of GLUT1 by endothelial cells in IH, as it is upregulated by HIF-1 [13]. Interestingly, propranolol has recently been shown to reduce the chance of disease progression in retinopathy of prematurity [14]. The mechanism of action is thought to be analogous to the effect in IH in that β-blockade is thought to reduce vascular endothelial growth factor expression (and angiogenesis) within the hypoxic retina by inhibition of HIF-1 and nitric oxide synthase.…”

Adjuvant role of anti-angiogenic drugs in the management of head and neck arteriovenous malformations

“…Even Propranolol could prove useful in this sense as suggested by some recent researches on retinopathy of prematurity and tumour biology [5][6][7].…”

β-Adrenoceptor Blockade for Infantile Hemangioma Therapy: Do β₃-Adrenoceptors Play a Role?

“…In keeping with this suggestion, a decrease in nitric oxide (NO) levels, VEGF, and the release of proangiogenic factors was observed after β 3 -adrenoceptor blockade (with SR59230A and L-748337) in hypoxic retinal explants [66,88]. Moreover, treatment with L-748337 showed a reduction in tumor weight, volume, and growth via a decrease in cell proliferation, iNOS expression, and VEGF production and an increase in apoptosis [89][90][91]. The above findings, taken together, suggest that targeting β 3 -adrenoceptors might be relevant in the treatment of IH, since this receptor seems to be involved in the pathophysiology of IH.…”