Abstract
Retinopathy of prematurity (ROP) is a potentially blinding retinal neovascular disease. Prolactin (PRL) circulating levels are higher in ROP than in control patients and such imbalance is a predictive risk variable for ROP that may impact disease progression (Zepeda-Romero et al. Pediatric Res 2017). PRL accesses the retina from the systemic circulation and is pro-angiogenic but can be cleaved into anti-angiogenic PRL fragments (vasoinhibin). Like preterm infants, newborn mice have incomplete retinal vascularization at birth and exposure to high oxygen, mimicking supplemental oxygen given to premature infants for respiratory care, induces the loss of new blood vessels eventually leading to hypoxia-induced retinal neovascularization. Here, we have investigated whether raising circulating PRL levels modifies the neovascularization of the retina of newborn mice exposed to high-oxygen. Neovascularization was assessed in mice throughout the first 8 days after birth in flat-mounted retinas immunostained for blood vessels. At postnatal day 1 (P1) the retina is almost devoid of blood vessels, which originate from the optic nerve and migrate radially reaching the periphery at P8. Exposure of P6 mice and nursing mothers to hyperoxia (75% oxygen) inhibited retinal vessel growth as determined by a significant (p<0.01) 50% reduction in retinal vascular density and expression of the endothelial cell markers, CD31 and VEGF receptor 2. Treatment with PRL (2 µg/g i.p. twice a day from P5 to P8) elevated PRL levels in serum (>300 ng/ml) and reduced hyperoxia-induced inhibition of retinal neovascularization, as revealed by a significant increase (p<0.03) in retinal vascular density and expression of endothelial cell markers. Current studies are addressing whether the pro-angiogenic effect of PRL is favored by its lower retinal conversion to vasoinhibin under hyperoxic conditions. These findings indicate that high levels of systemic PRL increase the vascularization of the neonatal mouse retina under conditions mimicking an early phase of ROP and support clinical studies suggesting the impact of PRL on disease progression. Supported by CONACYT grant 289568.