In conclusion, our findings demonstrate that endothelial Sp1/Sp3 plays a vital role in angiogenesis by inhibiting NOTCH1 transcription and provides insights into endothelial Sp1/Sp3 as a potential target for therapy in various angiogenesis-related disorders, including retinal diseases, CLI, and even tumors. This evidence concerns the gene NOTCH1 and Abnormal retinal morphology.