Decoupling Oxygen Tension From Retinal Vascularization as a New Perspective for Management of Retinopathy of Prematurity. New Opportunities From β-adrenoceptors

Abstract

Retinopathy of prematurity (ROP) is an evolutive and potentially blinding eye disease that affects preterm newborns. Unfortunately, until now no conservative therapy of active ROP with proven efficacy is available. Although ROP is a multifactorial disease, premature exposition to oxygen concentrations higher than those intrauterine, represents the initial pathogenetic trigger. The increase of oxygenation in a retina still incompletely vascularized promotes the downregulation of proangiogenic factors and finally the interruption of vascularization (ischemic phase). However, the increasing metabolic requirement of the ischemic retina induces, over the following weeks, a progressive hypoxia that specularly increases the levels of proangiogenic factors finally leading to proliferative retinopathy (proliferative phase). Considering non-modifiable the coupling between oxygen levels and vascularization, so far, neonatologists and ophthalmologists have "played defense", meticulously searching the minimum necessary concentration of oxygen for individual newborns, refining their diagnostic ability, adopting a careful monitoring policy, ready to decisively intervene only in a very advanced stage of disease progression. However, recent advances have demonstrated the possibility to pharmacologically modulate the relationship between oxygen and vascularization, opening thus the perspective for new therapeutic or preventive opportunities. The perspective of a shift from a defensive towards an attack strategy is now at hand.

Keywords: hyperoxia/hypoxia; hypoxia-inducible factor-1; prolyl hydroxylase domain-containing proteins; propranolol; β-adrenergic system.

FIGURE 1

Role of oxygen in the physiologic retinal vascularization and in the pathogenesis of ROP. During the intrauterine life, the physiologic low tension of oxygen promotes Hypoxia-Inducible Factor-1α (HIF-1α) and consequently Vascular-Endothelial Growth Factor (VEGF) upregulation, favoring the physiologic vascularization of retina (A) Premature oxygen exposition of preterm newborns induces the stop or even the regression of the immature retinal vascularization, secondary to the downregulation of both HIF-1α and VEGF (ischemic phase of ROP) (B) This progressive ischemia is responsible for the shift towards a retina that progressively becomes again hypoxic. Retinal hypoxia in turn induces HIF-1α and VEGF upregulation that promote a tumultuous and pathologic retinal neovascularization (proliferative phase of ROP) (C).

FIGURE 2

Current perspective and futuristic scenarios for ROP prevention and treatment. During the ischemic phase of ROP, futuristic are the hypotheses to prevent ROP occurrence through prolyl hydroxylase domain-containing proteins (PHD) inhibitors or β-adrenoceptor (β-AR) agonists aiming at preventing hyperoxia-induced vascular regression thus hindering the proliferative phase of ROP. The shift from hyperoxia to hypoxia is characterized by HIF-1α upregulation, which promotes VEGF production leading to retinal vessel proliferation. Concurrently, noradrenaline (NA) surge activates β2-ARs, expressed by Müller cells and β3-ARs, localized to endothelial cells, both participating to VEGF accumulation. Blockade of β2-ARs with propranolol is the goal of the current perspective to counteract ROP progression, while the futuristic approach of antagonizing β3-ARs deserves further investigations.