Targeting Runx1 in Pathological Retinal Angiogenesis: A Potential Therapeutic Approach.

PURPOSE

Neovascular eye diseases, such as proliferative diabetic retinopathy (PDR), wet age-related macular degeneration (wAMD) and retinopathy of prematurity (ROP), are major causes of vision loss and blindness worldwide. Our transcription factor motif enrichment analysis highlighted RUNX1 as a key regulator in the hypoxic response. The purpose of this study was to characterize how loss of Runx1 affects physiological and pathological retinal vasculature formation.

METHODS

RNA-seq analysis and Transcription factor motif enrichment analysis were conducted in hypoxic and normoxic HUVECs. Conditional deletion of Runx1 in endothelial cells In mice was achieved using recombinase driver Cdh5-CreERT2. Vascular coverage, density, vessel progression, branchpoints, and sprout numbers was measured in retina of Runx1iECKO mice. The expression patterns, functions, and potential therapeutic value of RUNX1 were further explored with clinical samples, as well as in vivo and in vitro experiments. Bioinformatics and high-throughput sequencing were performed to identify potential target genes of Runx1. RT-qPCR and Western blot analyses were carried out to detect the changes of PI3-kinase/AKT/mTOR pathway.

RESULTS

Loss of Runx1 in mice resulted in a reduction of the vascular coverage, density, vessel progression, branchpoints, and sprouts numbers of the retinal vascular network during its development. Notably, mature blood vessels remained unaffected by Runx1 inhibition. Upregulation of RUNX1 was observed in patients with PDR and ROP. RUNX1 Inhibition reduced endothelial cell proliferation, migration and tubule formation, leading to decreased pathological neovascularization, which is shown in oxygen-induced retinopathy. Mechanistically, in vitro experiments demonstrated that RUNX1 regulates EC angiogenesis through the PI3K/AKT/mTOR signaling pathway.

CONCLUSIONS

Runx1 is essential for physiological retinal vascularization. RUNX1 Inhibition may effectively decrease pathological neovascularization. Our findings suggest that targeting RUNX1 could be a promising therapeutic strategy for retinal neovascular disorders, preserving the integrity of mature blood vessels while selectively inhibiting neovascularization.