Abstract Body (Do not enter title and authors here): Cardiovascular disease (CVD) occurs 15 years earlier in patients with diabetes as compared to those without, but the underlying mechanisms remains incompletely understood. Endothelial cells (ECs) and macrophages (Mf) are key players in vascular wall and their interplay is highly heterogeneous and crucial in diabetic vasculopathy. Here, we leveraged human mesenteric arteries of varied diabetic state and used single cell (sc)- and spatial transcriptome mapping to interrogate the functional crosstalk between Mf subtypes and ECs in diabetes. We identified specific diabetes-induced EC-Mf interactions and explored their consequences in the context of peripheral artery disease (PAD).
Integrative scRNA-seq and spatial transcriptome (Visium) profiling identified a remarkable increase of Mf subtype expressing triggering receptor expressed on myeloid cells (TREM2) with concomitant increased EC-derived TREM2 ligands in human diabetic vs non-diabetic vessels. Such induction of TREM2 was consistently observed in arteries from type I and II diabetes mouse models. Conditioned medium from high glucose–cultured Mf, compared to that from normal glucose reduced EC migration and increased inflammatory markers, which were reversed by the medium from Mf with TREM2-knockdown. We further evaluated the functional importance of EC-TREM2 interaction in vivo in a mouse hindlimb ischemia (HLI) model. In diabetic mice subjected to HLI, a TREM2 neutralizing antibody promoted tissue recovery and perfusion. Finally, we showed that TREM2 was increased, especially in proximity to ECs, in ischemic sites, as compared to non-ischemic regions in limb muscles from human PAD patients.
Taken together, our study presents a diabetic artery atlas and identifies EC-TREM2 interaction as a crucial event in DACVDs, such as PAD. Our findings provide novel insights into the EC-Mf interplay in diabetes and vascular inflammation and how these cellular interactions may be targeted to ameliorate CVD.