Emerging opportunities in ROP therapy: from inhibiting pathological vessel growth to promoting physiological vascularization.

Despite continuous advances in the care of preterm infants, therapeutic management of ROP has made limited progress in recent years and remains a source of frustration for neonatologists. The current approach largely relies on the spontaneous resolution of the disease, limiting clinical intervention to observation and monitoring, with little capacity to significantly intervene on the pathological progression of retinal vascularization. Similarly, ophthalmologists often adopt a watchful waiting strategy, with invasive treatments reserved only for preventing imminent retinal detachment. As a result, ROP remains an orphan disease in terms of targeted pharmacological therapies that address its underlying pathophysiological mechanisms. However, recent years have brought significant advances in understanding the biological mechanisms that regulate retinal vascularization, pointing to the catecholaminergic stimulation of specific β-adrenoceptors (β-ARs). Indeed, after birth, β2-ARs appear to play a predominant role in coupling hypoxia to excessive vascular growth in the proliferative phase of ROP as it occurs in infantile hemangioma in which β2-AR blockade with propranolol, a non-selective β-AR antagonist, is the treatment of choice to prevent chaotic vessel proliferation. In this line, propranolol-based ophthalmic solutions may offer a promising balance of efficacy and safety in ROP. However, preclinical studies have shown that β2-AR blockade with propranolol suppresses pathological vascularization without promoting vessel regrowth in the avascular area. Additional therapeutic opportunities can be provided by our project regarding the role of β3-AR activation in promoting the revascularization of the central retina otherwise vaso-obliterated in response to hyperoxia, through recovered astrocyte template, which is likely to play an important role in vasculature recovery. This possibility paves the way for preventive pharmacological strategies using β3-AR agonists against ROP. It is likely that in the coming years an approach similar to that leading to explore the potential of propranolol in ROP, might be used to extend to preterm infants the results of preclinical studies on the efficacy of β3-AR agonism. In this case, the goal would be to stimulate the physiological process of vascularization rather than to slowing down the progression of ROP.