By deciphering molecular crosstalk between immune and endothelial cells, a team has uncovered how diabetes leads to breakdowns in blood vessels in the limbs. “Overall, the work […] advances our mechanistic understanding of [type 2 diabetes]-driven [peripheral artery disease] and has laid the foundation for developing targeted therapies for a disease with few viable treatment options,” write Michael Chang and colleagues in a related Focus. Affecting more than half a billion people worldwide, diabetes has become one of the single greatest burdens on health and longevity. One common complication is peripheral artery disease, which restricts blood flow to the arms and legs and can eventually lead to amputation in severe cases. Despite this danger, there are few effective therapies for peripheral artery disease, in part because scientists don’t fully grasp the mechanisms that drive blood vessel dysfunction on the molecular level. However, researchers suspect that endothelial cells and macrophages are chief contributors. In this study, Naseeb Malhi and colleagues harnessed single-cell RNA sequencing and spatial transcriptomics to build an atlas of the diabetic blood vessel. They profiled vessel cells in postmortem artery samples from the mesentery of five donors with type 2 diabetes and five healthy donors. While drawing their atlas, they discovered that the expression of a gene named TREM2 closely correlated with type 2 diabetes. This gene encodes a receptor named TREM2, which was unusually active on immune cells called mononuclear phagocytes. Further work showed that these cells displayed “foamy” features and adopted a pro-inflammatory phenotype, and that endothelial cells bore high quantities of ligands that bind TREM2. The team analyzed clinical samples and discovered evidence of endothelial cell-TREM2 signaling in samples from patients with peripheral artery disease. Malhi et al. also showed that blocking TREM2 with an antibody improved blood vessel flow in a mouse model of peripheral artery disease, suggesting that TREM2 should be explored as a future therapeutic target.
