The protection of mesenchymal stem cells in metabolic reprogramming and endothelial-mesenchymal transition in diabetic aortas

Abstract Vascular remodeling, a precursor to atherosclerosis and coronary heart disease, is associated with high morbidity and mortality in individuals with diabetes. The roles of endothelial-mesenchymal transition (EndMT) and human umbilical cord mesenchymal stem cells (hUCMSCs) in this process remain unclear. In this study, we used db/db mice as a diabetic model to investigate the effect of hUCMSCs on metabolic reprogramming and vascular remodeling. We analyzed serum markers, tissue morphology, metabolomics, and endothelial cell-specific proteomics. The results demonstrated that vascular remodeling and EndMT were exacerbated in diabetes and alleviated by hUCMSCs. Metabolomic analysis identified 209 altered metabolites. Most metabolic intermediates were increased, while anti-inflammatory metabolites such as arachidonoyl ethanolamide and sphingosine were decreased in the diabetic state. Treatment with hUCMSCs restored these metabolites to near-normal levels, thereby improving metabolic reprogramming and the vascular microenvironment. Correspondingly, endothelial cell proteomics revealed increased levels of glycolytic enzymes, inflammatory factors, and EndMT markers, including mitogen-activated protein kinase kinase kinase 20 (Map3k20), disintegrin and metalloproteinase domain-containing protein 10 (Adam10), and integrin alpha-8 (Itga8), in diabetes; hUCMSC treatment downregulated these factors. Notably, KEGG and protein–protein interaction analyses indicated that hUCMSCs inhibited the Tgfb1i1/Rock1 axis within the TGF-beta pathway, which drives EndMT. We further verified the expression of these proteins through endothelial immunofluorescent co-staining and confirmed the role of Rock1 in high glucose-induced EndMT in vitro. This study elucidates a potential molecular mechanism and a therapeutic strategy for early atherosclerosis in diabetes and provides a foundation for evaluating endothelial states in vivo.