Abstract
Purpose :
Retinal neovascularization (NV) leads to various pathological conditions, such as retinopathy of prematurity (ROP), diabetic retinopathy (DR), and age-related macular degeneration (AMD). Although anti-VEGF therapy for retinal NV treatment is successful, but it also co-exists with various side effects. Various studies have shown that deletion of A Disintegrin and metalloproteinase domain-containing protein (ADAM10) is embryonically lethal and results in organ-specific vascular defects, but little is known regarding its role in proliferative retinopathies.
Methods :
We have used human retinal microvascular endothelial cells (HRMVECs) and Oxygen induced retinopathy (OIR) as models to understand the role of ADAM10 in proliferative/ischemic retinopathies. To comprehend the role of ADAM10 in retinal NV, endothelial cell-specific ADAM10 conditional knock-out mice were generated. At P13, P15, and P17, eyes were enucleated, and retinas were isolated and evaluated for retinal NV, avascular area, tip cell formation, and proliferation. The effect of ADAM10 on notch signaling and angiogenesis was analyzed at a molecular level by depleting ADAM10 levels in HRMVECs. In addition, we used 3’ mRNA sequencing, human phospho-RTKs and human Angiogenesis Proteome Profiler assays to assess ADAM10 mediated angiogenic signaling involved in HRMVECs angiogenic events.
Results :
We observed a significant reduction in retinal NV in endothelial-specific ADAM10 knock-out mice (ADAM10iΔEC) compared to the C57BL/6 (WT) mice. We also observed that hypoxia-induced vascular leakage and edema were significantly reduced in ADAM10iΔEC mice compared to WT mice. Endothelial cell sprouting was also significantly decreased in ADAM10iΔEC mice. Our findings also emphasize that ADAM10-mediated retinal NV is independent of notch signaling. Our sequencing data revealed that the depletion of ADAM10 results in the downregulation of various angiogenic genes, including EFNB2/ EphB2. Studies have shown that EFNB2/ EphB2 regulates developmental angiogenesis, but its role in pathological retinal neovascularization is not well reported. We observed downregulation of EphB2/EFNB2 in ADAM10iΔEC mice, which might suggest its probable regulation by ADAM10 in retinal neovascularization.
Conclusions :
Our findings provide evidence that ADAM10 might be used as a therapeutic agent for retinal neovascularization.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.