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These culminate in impaired coronary blood flow. To interrogate transcriptional differences potentially contributing to CMD, we tested the hypothesis that comprehensive single-cell and spatial transcriptomic profiling of the coronary microcirculation and surrounding myocardium will identify new pathways to target in CMD. We utilized an innovative combination of single-cell RNA profiling and spatial transcriptomics to examine transcriptional differences and molecular signatures of CMD in T2D mice. Single-cell RNA profiling and spatial transcriptomics revealed an upregulation of genes linked to adipogenesis, fatty acid metabolism, and oxidative phosphorylation in T2D cell clusters and coronary microvascular-enriched regions. In ECs, VSMCs, cardiomyocyte clusters, fibroblasts, and macrophages, the upregulation of adipogenesis was directed by\n                    <jats:italic>Angplt4<\/jats:italic>\n                    and\n                    <jats:italic>Ephx2<\/jats:italic>\n                    , whereas\n                    <jats:italic>Hmgcs2<\/jats:italic>\n                    and\n                    <jats:italic>Acot2<\/jats:italic>\n                    were the key players in the upregulation of fatty acid metabolism, and\n                    <jats:italic>Pdk4<\/jats:italic>\n                    and\n                    <jats:italic>Ech1<\/jats:italic>\n                    were the drivers of oxidative phosphorylation upregulation. These intriguing data support the well-documented concept that cardiac metabolic inflexibility in T2D heart failure\u2014characterized by reduced mitochondrial function, increased reliance on fatty acid oxidation, and impaired glucose utilization\u2014contributes to oxidative stress and lipotoxicity. Our data unveiled novel and unique gene expression signatures of coronary microvessels in the presence and absence of diabetes.\n                  <\/jats:p>","DOI":"10.1007\/s00395-025-01144-7","type":"journal-article","created":{"date-parts":[[2025,11,7]],"date-time":"2025-11-07T18:11:35Z","timestamp":1762539095000},"page":"1109-1129","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Single cell and spatial transcriptomic profiling of the type 2 diabetic coronary microcirculation and myocardium"],"prefix":"10.1007","volume":"120","author":[{"given":"Patricia E.","family":"McCallinhart","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corinne H.","family":"Strawser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth A. 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