Propranolol ameliorates retinopathy of prematurity in mice by downregulating HIF-1α via the PI3K/Akt/ERK pathway

Background Retinopathy of prematurity (ROP) is the leading cause of blindness in infants, and elevation of HIF-1 alpha through the PI3K/Akt and ERK pathways is implicated in ROP pathogenesis. The mechanism of action of propranolol in ROP remains controversial. We investigated the effect of propranolol on ROP and explored its potential mechanisms of action in an oxygen-induced retinopathy (OIR) mouse model. Methods OIR mice were first treated with propranolol intraperitoneally, and the retina integrity was measured by FITC-dextran and hematoxylin-eosin staining. The expression of HIF-1 alpha, VEGF, and key signaling pathway proteins was determined using real-time PCR and western blotting. Results FITC-dextran staining showed that propranolol treatment reduced damage to retinal morphology in OIR mice. Mice treated with propranolol showed a reduced number of nuclei of vascular endothelial cells penetrating the inner limiting membrane of the retina, confirming the therapeutic effect of propranolol on ROP. Further analysis showed that HIF-1 alpha and PI3K/Akt/ERK pathway protein levels were significantly elevated in OIR mice. In contrast, propranolol treatment downregulated the expression of these proteins, indicating that the PI3K/Akt/ERK/HIF-1 alpha axis is associated with propranolol-induced ROP alleviation. Conclusions Propranolol has a therapeutic function against ROP, likely through the downregulation of HIF-1 alpha via the PI3K/Akt/ERK pathway. Impact Propranolol can reduce the formation of abnormal retinal neovascularization in oxygen-induced retinopathy (OIR) models, and reduce leaking, tortuous, and abnormally expanding retinal blood vessels. Propranolol possibly improves OIR by inhibiting the activated ERK and HIF-1 alpha pathways. Furthermore, propranolol may downregulate HIF-1 alpha via the PI3K/Akt/ERK pathway to ameliorate retinopathy of prematurity. This study elucidated that the therapeutic effect of propranolol in OIR mice does not involve the VEGFR-2 pathway.