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Transl. Med."],"published-print":{"date-parts":[[2026,4,22]]},"abstract":"<jats:p>\n                    Diabetes mellitus (DM) accelerates vascular diseases including peripheral arterial disease (PAD). Endothelial cells (ECs) and macrophages (M\u03a6s) 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 M\u03a6s, 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\n                    <jats:italic toggle=\"yes\">triggering receptor expressed on myeloid cells 2<\/jats:italic>\n                    (\n                    <jats:italic toggle=\"yes\">TREM2<\/jats:italic>\n                    ) as one of the top T2D-induced genes in mononuclear phagocytes (MPs), with concomitant increases in TREM2 ligands in ECs. TREM2\n                    <jats:sup>+<\/jats:sup>\n                    MPs exhibited foam cell\u2013like 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\u2013induced 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.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.adu3761","type":"journal-article","created":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T17:58:42Z","timestamp":1776880722000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":6,"title":["Diabetes-induced TREM2\u2013endothelial cell signaling impairs ischemic vascular repair"],"prefix":"10.1126","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8981-2974","authenticated-orcid":true,"given":"Naseeb Kaur","family":"Malhi","sequence":"first","affiliation":[{"name":"Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute and Beckman Research Institute of City of Hope, Duarte, CA 91010, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2271-3725","authenticated-orcid":true,"given":"Yingjun","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute and Beckman Research Institute of City of Hope, Duarte, CA 91010, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-6549-0163","authenticated-orcid":true,"given":"Muxi","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute and Beckman Research Institute of City of Hope, Duarte, CA 91010, USA."},{"name":"Irell and Manella Graduate School of Biological Sciences, City of Hope, Duarte, CA 91010, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaofang","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute and Beckman Research Institute of City of Hope, Duarte, CA 91010, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongqiang","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute and Beckman Research Institute of City of Hope, Duarte, CA 91010, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3805-6144","authenticated-orcid":true,"given":"Rahuljeet Singh","family":"Chadha","sequence":"additional","affiliation":[{"name":"Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3123-9159","authenticated-orcid":true,"given":"Alonso","family":"Tapia","sequence":"additional","affiliation":[{"name":"Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute and Beckman Research Institute of City of Hope, Duarte, CA 91010, USA."},{"name":"Irell and Manella Graduate School of Biological Sciences, City of Hope, Duarte, CA 91010, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shufan","family":"Yin","sequence":"additional","affiliation":[{"name":"Nancy E. and Peter C. 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