Year: 2024
Type: article
Abstract: Neovascularization is implicated in the pathology of retinopathy of prematurity (ROP), diabetic retinopathy (DR), and age-related macular degeneration (AMD), which are the leading causes of blindness worldwide. In our work, we analyzed how heme released during hemorrhage affects hypoxic response and neovascularization. Our retrospective clinical analysis demonstrated, that hemorrhage was associated with more severe retinal neovascularization in ROP patients. Our heme-stimulated human retinal pigment epithelial (ARPE-19) cell studies demonstrated increased expression of positive regulators of angiogenesis, including vascular endothelial growth factor-A (VEGFA), a key player of ROP, DR and AMD, and highlighted the activation of the PI3K/AKT/mTOR/VEGFA pathway involved in angiogenesis in response to heme. Furthermore, heme decreased oxidative phosphorylation in the mitochondria, augmented glycolysis, facilitated HIF-1α nuclear translocation, and increased VEGFA/GLUT1/PDK1 expression suggesting HIF-1α-driven hypoxic response in ARPE-19 cells without effecting the metabolism of reactive oxygen species. Inhibitors of HIF-1α, PI3K and suppression of mTOR pathway by clinically promising drug, rapamycin, mitigated heme-provoked cellular response. Our data proved that oxidatively modified forms of hemoglobin can be sources of heme to induce VEGFA during retinal hemorrhage. We propose that hemorrhage is involved in the pathology of ROP, DR, and AMD.
Source: Redox Biology
Language: English
Subfield: Radiology, Nuclear Medicine and Imaging
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,900
Funders: Hungarian Research Network, American Hungarian Foundation, European Commission, European Geosciences Union, Ministry of Science, Technology and Space, Hungarian Scientific Research Fund, Magyar Tudományos Akadémia, Debreceni Egyetem, Magyarország Kormánya, Nemzeti Kutatási, Fejlesztési és Innovaciós Alap, National Research, Development and Innovation Office, European Social Fund
Awards: G1252719238, G1295621590, G1306406062, G1348732877, G1679570784, G203622017, G2744728761, G2758498933, G2790654766, G2921894577, G298428782, G3370310483, G3463726684, G3809123898, G4028950358, G4291881689, G4875182801, G5205327413, G525072561, G603472522, G6179861421, G61955116, G6704897549, G6738607125, G7015593406, G7360783662, G7694217703, G7755999571, G7966265063, G8070946637, G8297231142, G8491279977, G8834782930
OpenAlex ID: W4401651080