This design is based on three premises: (1) hyperglycemia and chronic inflammation are two key culprits in diabetes to cause EC dysfunction17,18; (2) the prolonged and combined treatment would induce robust EC changes, encompassing eNOS suppression, pro-inflammatory activation, ECM remodeling, and EndoMT, in which ECs manifest a phenotypic transition into mesenchymal-like cells19,20; and (3) the time course will allow temporal mapping of EC changes in transcriptome, genomic interactions, and RNA–genome interactions. This evidence concerns the gene NOS3 and diabetes mellitus.