Heme: a link between hemorrhage and retinopathy of prematurity progression.

Retinopathy of prematurity (ROP) is a vision-threatening condition caused by abnormal retinal vascular development. To date, no studies have investigated the role of hemorrhage in neovascularization in ROP. During our retrospective clinical analysis, we found that hemorrhage was associated with more severe retinal neovascularization. Transcriptional changes in the expression of positive regulators of angiogenesis, including vascular endothelial growth factor (VEGF), a key player of ROP and diabetic retinopathy (DR), were detected by RNA sequencing of heme-stimulated human retinal pigment epithelial (hRPE) cells. Our results highlight the activation of the PI3K/AKT/mTOR/VEGF pathway involved in angiogenesis in response to heme. Furthermore, heme decreased oxidative phosphorylation in the mitochondria, augmented glycolysis, facilitated HIF-1a nuclear translocation, and increased VEGF/GLUT1/PDK1 expression suggesting HIF-1a-driven hypoxic response in hRPEs. Inhibitors of HIF-1a, PI3K and suppression of mTOR pathway by clinically promising drug, rapamycin, mitigated heme-provoke cellular response. We propose that hemorrhage is involved in the pathology of ROP and DR.