Endothelial dysfunction in human diabetic vascular complications: translating single-cell transcriptomics into therapeutic opportunities.

Type 2 diabetes mellitus (T2DM) is increasingly recognized as a systemic vascular disease in which endothelial cell (EC) dysfunction is a central driver of diabetic vascular complications (DVCs), which account for most diabetes-related morbidity and mortality. Although conventional therapies improve glycemic control and reduce some cardiovascular risk, they do not fully prevent microvascular and macrovascular injury, highlighting the need for more precise vascular-targeted strategies. Recent advances in single-cell RNA sequencing have transformed our understanding of diabetic endothelial biology by resolving EC heterogeneity at unprecedented resolution across human tissues, yet insights from human diabetic tissues remain fragmented. Here, we provide a cross-tissue synthesis of currently available human single-cell studies profiling ECs across diabetic vasculature, focusing on diabetic arteries, diabetic retinopathy, diabetic nephropathy, and diabetic foot ulcers to define mechanisms underlying dysfunctional EC states in different DVCs. We propose a unifying framework in which DVCs are driven by tissue-specific endothelial-state transitions arising from combinations of epigenetic, transcriptional, post-translational, and intercellular signaling programs, rather than by isolated pathway abnormalities. These include a pro-inflammatory, pro-fibrotic, and anti-angiogenic state in diabetic arteries; a pathological angiogenic and barrier-disruptive inflammatory state in diabetic retinopathy; a pro-fibrotic and maladaptive angiogenic/proliferative state in diabetic nephropathy; and an inflammatory, anti-angiogenic state in diabetic foot ulcers. This framework also provides a mechanistic explanation for the limited efficacy of current single-pathway therapies, including VEGF-centered approaches, and uncovers VEGF-independent mechanisms that may be therapeutically actionable for these DVCs. Importantly, this review not only highlights the need for but also proposes combination therapeutic strategies that target multiple regulatory layers within tissue-specific endothelial states. Overall, this review supports a paradigm shift toward vascular bed-specific, combinatorial, and state-directed therapeutic strategies to reprogram endothelial dysfunction in DVCs.