Diabetes-induced TREM2-endothelial cell signaling impairs ischemic vascular repair

Diabetes mellitus (DM) accelerates vascular diseases including peripheral arterial disease (PAD). Endothelial cells (ECs) and macrophages (MΦs) are important contributors to DM-associated vascular dysfunction, both individually and through reciprocal cross-talk. Although single-cell profiling has revealed the heterogeneity of ECs and MΦs, how this diversity translates into cell-cell interactions, and consequentially vascular function, remains unclear. We leveraged single-cell RNA sequencing and spatial transcriptomics to profile human mesenteric arteries from non-diabetic donors and from donors with type 2 diabetes (T2D), generating a transcriptome and interactome atlas of diabetic vasculature. This analysis identified triggering receptor expressed on myeloid cells 2 (TREM2) as one of the top T2D-induced genes in mononuclear phagocytes (MPs), with concomitant increases in TREM2 ligands in ECs. TREM2⁺ MPs exhibited foam cell-like features but acquired a proinflammatory gene profile in DM. Functionally, TREM2 inhibition in vitro attenuated proinflammatory responses in MPs and ECs and enhanced EC migration. In streptozotocin- and high-fat high-sucrose diet-induced mouse models of diabetes with hindlimb ischemia (a model of PAD), TREM2 blockade using a neutralizing antibody improved perfusion recovery, whereas TREM2 activation with an agonist exacerbated ischemic injury. Analysis of clinical samples confirmed elevated EC-TREM2 signaling in human PAD, particularly in the setting of DM, highlighting its translational relevance. Collectively, our study presents an atlas of human diabetic vessels with single-cell and spatial resolution, identifying TREM2-EC interaction as a driver of diabetic vasculopathy and a potential therapeutic target in DM-associated PAD.