Abstract
Purpose :
Retinal vaso-obliteration is associated with an inability of Endothelial Progenitor Cells (EPCs) to promotes vasculogenesis in oxygen-induced retinopathy (OIR). Because interleukine-1b (IL-1b) is convincingly reported as an important pro-inflammatory factor contributing to vascular degeneration during OIR, we investigated the potential beneficial effects of rytvela (a new non-competitive allosteric (IL)-1 receptor inhibitor) on the post-transcriptional mechanism involved EPC dysfunction during OIR.
Methods :
The effect of rytvela on the bioactivity of EPCs subjected to hyperoxia (80% O2) or IL-1b stimulation (100ng/mL), has been examined by senescence, migration and vasculogenic assay. We next profiled micro-RNAs (miRs) expression using next generation sequencing (NGS), in the same condition to identify the post-transcriptional mechanisms associated with EPC dysfunction.
Results :
First, we found that EPCs subjected to hyperoxia or IL-1b exhibit a phenotype of early senescence, associated with a significant decrease of their migratory and vasculogenic properties. Interestingly, rytvela inhibits hyperoxia/IL-1b-induced EPC-senescence and rescued their migration and tubulogenic function. At post-transcriptional level, NGS analysis reveal that 26 miRs are significantly modulated by both IL-1b and hyperoxia, and the expression of 9 of these miRs are recovered by rytvela. Interestingly we found that miR-875 - predicted to negatively regulate the expression of FOXF1, a key transcriptional factor for multiple pro-angiogenic genes including CXCR4 – to be upregulated. We next performed a gain-and-loss of function to study the precise role of miR-875 on EPC bioactivity. The result confirms that overexpression of miR-875 in native EPCs leads to downregulation of FOXF1/CXCR4 signaling, that in turn decreases the migratory and vasculogenic properties of native EPCs. Conversely, inhibition of miR-875 protects EPCs functions against OIR conditions by restoring FOXF1/CXCR4 expression.
Conclusions :
Altogether, our results suggest that rytvela can protect vasculogenic properties of EPCs in OIR conditions. Bioengineering EPCs with rytvela or antagomiR-875 based-therapy could provide a new potential strategy to preserve vessel integrity in ischemic retinopathies.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.