Single-cell insights into maladaptive endothelial plasticity and therapeutic targets in diabetic vascular...

Endothelial plasticity, the capacity of endothelial cells (ECs) to reversibly alter their phenotype in response to environmental cues, typically enables adaptive vascular remodeling and tissue homeostasis. In diabetes, this plasticity becomes maladaptive, driving pathological transitions across interconnected axes: dysregulated angiogenesis with barrier destabilization, inflammatory reprogramming through immune-endothelial crosstalk, metabolic dysfunction spanning mitochondrial stress to senescence, and endothelial-to-mesenchymal transition with fibrosis. In this review, we synthesize mechanistic insights across endothelial state transitions and highlight how single-cell approaches have reframed diabetic vascular disease as a disorder of maladaptive endothelial plasticity. By integrating single-cell insights from diabetic mouse models and human patient samples, we demonstrate that restoring adaptive endothelial plasticity requires coordinated multi-dimensional intervention targeting the intersecting pathways that perpetuate pathological transitions, timed to disease stage and calibrated to vascular bed-specific context. For example, combining metabolic therapies such as GLP-1 receptor agonists or SGLT2 inhibitors with anti-inflammatory agents targeting IL-17A or IL-1β, pairing anti-VEGF treatments with inhibitors of MFAP4 or ANGPTL4 to overcome angiogenic bypass pathways, or coupling senolytics, such as UBX1325, with anti-fibrotic strategies like TGF-β or SETD7 inhibition to prevent irreversible EndoMT. We identify candidate therapeutic targets across angiogenic, inflammatory, metabolic, and fibrotic domains, and highlight critical knowledge gaps, most notably the limited characterization of human diabetic ECs, that must be addressed to translate these insights into effective clinical strategies for preventing diabetic vascular complications.