Abstract
Purpose :
Endothelial Progenitor Cells (EPCs) can actively participate in revascularization in retinopathy of prematurity (ROP). However, the mechanisms involved in the dysfunction of EPCs, particularly in the oxygen-induced retinopathy (OIR) model of ROP is unclear. Interestingly, Nogo-A, a member of the reticulon family whose function are traditionally related as an inhibitor of neurite regeneration in the central nervous system, has recently been documented to negatively control angiogenesis as a repellent agent. However, the potential deleterious impact of Nogo-A in EPC activity has so far not been addressed. This study aims to investigate the interrelation between EPC function and Nogo-signaling in OIR.
Methods :
The effect of NOGO-A suppression (using an antagonist peptide) on the bioactivity of EPCs subjected to hyperoxia (80% O2) has been examined by migration and vasculogenic assay. Expression of angiogenic factors was analyzed by qRT-PCR and western blot. In vivo, the effect of intraperitoneal injection of native or reprogrammed EPCs (Nogo pre-inhibited) in OIR rats at P5 (prior to exposure to hyperoxia) was performed to analyzed retinal vaso-obliteration.
Results :
We found that the expression of Nogo-A and its specific receptor NgR1 are significantly increased in isolated EPCs subjected to hyperoxia as well as in EPCs isolated from OIR rats, compared to respective control. EPCs subjected to hyperoxia display reduced migratory and tubulogenic ability; conversely, inhibition of Nogo-A rescued the curtailed function of EPCs subjected to hyperoxia. In addition, Nogo-A neutralization led to increased intracellular levels of SDF-1 in EPCs - an important factor involved in EPCs migration and bone-marrow mobilization to vessels located in ischemic areas. In vivo, intraperitoneal injection of reprogrammed EPCs in OIR rats at P5 prevented retinal vaso-obliteration at P10 (peak timing for vaso-obliteration); this was not the case in rats injected with native EPCs; this was associated with increased retinal expression of key angiogenic factors including VEGF and SDF-1.
Conclusions :
Altogether, the results suggest that hyperoxia alters the angiogenic function of EPCs in part by inducing Nogo-A signaling which participates in curtailing retinal vascularization during OIR. Hence, Nogo-A in EPCs is a potentially new target to preserve vascular integrity in ischemic retinopathies.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.