Abstract Body: Diabetes mellitus (DM) markedly accelerates vascular disease progression, including peripheral arterial disease (PAD), yet the cellular mechanisms linking diabetes to impaired vascular repair remain incompletely defined. Endothelial cells (ECs) and macrophages (MΦs) are central contributors to diabetic vascular dysfunction, both through cell-intrinsic alterations and reciprocal intercellular signaling. While single-cell transcriptomic studies have revealed substantial EC and MΦ heterogeneity, how this diversity translates into functional cell–cell interactions in human diabetic vasculature remains unclear.
To address this, we integrated single-cell RNA sequencing and spatial transcriptomics to profile human mesenteric arteries from non-diabetic (ND) and type 2 diabetic (T2D) donors, generating a transcriptomic and interactome atlas of diabetic vessels. This analysis identified Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) as one of the most highly induced genes in mononuclear phagocytes (MPs) in T2D, accompanied by increased expression of TREM2 ligands in ECs. TREM2-positive MPs displayed foam cell–like features while adopting a distinct pro-inflammatory transcriptional profile in DM.
Functional studies demonstrated that TREM2 inhibition attenuated inflammatory signaling in both MPs and ECs and enhanced EC migratory capacity in vitro. In vivo, pharmacologic blockade of TREM2 significantly improved perfusion recovery in diabetic mice subjected to hindlimb ischemia, whereas TREM2 activation worsened ischemic injury. Importantly, analysis of human clinical PAD samples confirmed increased EC–TREM2 signaling within diseased vessels. Consistent with these tissue-level findings, circulating plasma TREM2 levels were significantly elevated in patients with PAD, with the highest levels observed in individuals with concomitant DM, underscoring the systemic and translational relevance of TREM2 signaling in diabetic vasculopathy.
Collectively, this study provides a single-cell and spatially resolved atlas of human diabetic vasculature and identifies TREM2-dependent EC–MP interactions as a key driver of diabetic vasculopathy. These findings highlight TREM2 as a mechanistic link between inflammation and impaired vascular repair and suggest its therapeutic potential in DM-associated PAD.