{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T01:59:42Z","timestamp":1785117582482,"version":"3.55.0"},"reference-count":108,"publisher":"IMR Press","issue":"5","license":[{"start":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T00:00:00Z","timestamp":1779667200000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"General Program of the National Natural Science Foundation of China","award":["82370438"],"award-info":[{"award-number":["82370438"]}]},{"name":"Interdisciplinary Research Cooperation Project Team Funding of Dalian Medical University","award":["JCHZ2023014"],"award-info":[{"award-number":["JCHZ2023014"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Rev. Cardiovasc. Med."],"abstract":"<jats:p>Mitochondria and endothelial cells engage in bidirectional crosstalk to maintain vascular tone, barrier integrity, and inflammatory quiescence. In cardiometabolic diseases (CMDs), metabolic overload and chronic inflammatory cues disrupt endothelial mitochondrial bioenergetics, dynamics, and quality-control mechanisms. As protective systems weaken, redox imbalance and impaired nitric oxide signaling\u2014further exacerbated by barrier dysfunction\u2014trigger endothelial activation and loss of homeostasis. Clinical translation has lagged largely because endothelial responses vary across vascular beds and microenvironments, and most clinical trials fail to align patient selection or endpoints with mitochondrial mechanisms. This review addresses a major translational gap: how mitochondrial stress programs map onto context-specific endothelial phenotypes in human CMDs, and how this mapping can inform the selection of actionable therapeutic strategies. Indeed, this review integrates single-cell and spatial multi-omics data to link mitochondrial stress and metabolic remodeling to specific anatomical niches, transforming the broad notion of \u201cendothelial dysfunction\u201d into defined biological programs for biomarker selection and target discovery. Moreover, this review categorizes translational opportunities by the strength of human evidence. Near-term priorities include repurposed cardiometabolic drugs (e.g., sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1(GLP-1) receptor agonists) and circulating biomarkers for patient stratification or pharmacodynamic monitoring (e.g., growth differentiation factor 15 (GDF15), cell-free mitochondrial DNA (cf-mtDNA), endothelium-derived extracellular vesicles). In contrast, gene and cell therapies, as well as advanced delivery and regenerative platforms, remain at the preclinical stage and require stronger mechanistic validation, improved safety profiles, and scalable delivery systems before clinical evaluation. Thus, a key unmet need is for multicenter, mechanism-informed trials that integrate endothelial functional endpoints (e.g., flow-mediated dilation (FMD)\/peripheral arterial tonometry (PAT) with mitochondrial-associated molecular readouts under harmonized protocols and standardized reference criteria to enhance reproducibility and cross-study comparability. Collectively, these insights establish mitochondrial\u2013endothelial biology as an evidence-based entry point for precision vascular medicine in CMDs.<\/jats:p>","DOI":"10.31083\/rcm47549","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T01:28:22Z","timestamp":1785115702000},"source":"Crossref","is-referenced-by-count":0,"title":["Mitochondrial-Endothelial Crosstalk in Cardiometabolic Disease: Mechanisms and Translational Opportunities in the Multi-omics Era"],"prefix":"10.31083","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-4748-6028","authenticated-orcid":true,"given":"Di","family":"Liu","sequence":"first","affiliation":[{"name":"The First Clinical College, Liaoning University of Traditional Chinese Medicine, 110847 Shenyang, Liaoning, China"},{"name":"Department of Cardiology, The Second Hospital of Dalian Medical University, 116023 Dalian, Liaoning, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-8744-2617","authenticated-orcid":true,"given":"Jiaxi","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The Second Hospital of Dalian Medical University, 116023 Dalian, Liaoning, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-1395-8372","authenticated-orcid":true,"given":"Yuwei","family":"He","sequence":"additional","affiliation":[{"name":"The First Clinical College, Liaoning University of Traditional Chinese Medicine, 110847 Shenyang, Liaoning, China"},{"name":"Department of Cardiology, The Second Hospital of Dalian Medical University, 116023 Dalian, Liaoning, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-4035-3099","authenticated-orcid":true,"given":"Yuhang","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The Second Hospital of Dalian Medical University, 116023 Dalian, Liaoning, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-2156-6305","authenticated-orcid":true,"given":"Mengjie","family":"Yin","sequence":"additional","affiliation":[{"name":"The First Clinical College, Liaoning University of Traditional Chinese Medicine, 110847 Shenyang, Liaoning, China"},{"name":"Department of Cardiology, The Second Hospital of Dalian Medical University, 116023 Dalian, Liaoning, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-6701-4662","authenticated-orcid":true,"given":"Jie","family":"Zhang","sequence":"additional","affiliation":[{"name":"The First Clinical College, Liaoning University of Traditional Chinese Medicine, 110847 Shenyang, Liaoning, China"},{"name":"Department of Cardiology, The Second Hospital of Dalian Medical University, 116023 Dalian, Liaoning, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3437-2120","authenticated-orcid":true,"given":"Xin","family":"Zhao","sequence":"additional","affiliation":[{"name":"The First Clinical College, Liaoning University of Traditional Chinese Medicine, 110847 Shenyang, Liaoning, China"},{"name":"Department of Cardiology, The Second Hospital of Dalian Medical University, 116023 Dalian, Liaoning, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2026,5,25]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Eroglu T, Capone F, Schiattarella GG. 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Journal of the American College of Cardiology. 2023; 82: 2350\u20132473.","DOI":"10.1016\/j.jacc.2023.11.007"},{"key":"ref4","doi-asserted-by":"publisher","unstructured":"Martin SS, Aday AW, Allen NB, Almarzooq ZI, Anderson CAM, Arora P, et al. 2025 Heart Disease and Stroke Statistics: A Report of US and Global Data From the American Heart Association. Circulation. 2025; 151: e41\u2013e660.","DOI":"10.1161\/CIR.0000000000001303"},{"key":"ref5","doi-asserted-by":"publisher","unstructured":"Gimbrone MA, Jr, Garc\u00eda-Carde\u00f1a G. Endothelial Cell Dysfunction and the Pathobiology of Atherosclerosis. Circulation Research. 2016; 118: 620\u2013636.","DOI":"10.1161\/CIRCRESAHA.115.306301"},{"key":"ref6","doi-asserted-by":"publisher","unstructured":"Gallo G, Savoia C. New Insights into Endothelial Dysfunction in Cardiometabolic Diseases: Potential Mechanisms and Clinical Implications. 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The Journal of Clinical Investigation. 2002; 109: 817\u2013826.","DOI":"10.1172\/JCI14442"},{"key":"ref16","doi-asserted-by":"publisher","unstructured":"Radi R. Oxygen radicals, nitric oxide, and peroxynitrite: Redox pathways in molecular medicine. Proceedings of the National Academy of Sciences of the United States of America. 2018; 115: 5839\u20135848.","DOI":"10.1073\/pnas.1804932115"},{"key":"ref17","doi-asserted-by":"publisher","unstructured":"Schulz E, Gori T, M\u00fcnzel T. Oxidative stress and endothelial dysfunction in hypertension. Hypertension Research: Official Journal of the Japanese Society of Hypertension. 2011; 34: 665\u2013673.","DOI":"10.1038\/hr.2011.39"},{"key":"ref18","doi-asserted-by":"publisher","unstructured":"BelAiba RS, Djordjevic T, Petry A, Diemer K, Bonello S, Banfi B, et al. NOX5 variants are functionally active in endothelial cells. 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Molecular mechanisms regulating the vascular prostacyclin pathways and their adaptation during pregnancy and in the newborn. Pharmacological Reviews. 2012; 64: 540\u2013582.","DOI":"10.1124\/pr.111.004770"},{"key":"ref22","doi-asserted-by":"publisher","unstructured":"Jyrkk\u00e4nen HK, Kansanen E, Inkala M, Kivel\u00e4 AM, Hurttila H, Heinonen SE, et al. Nrf2 regulates antioxidant gene expression evoked by oxidized phospholipids in endothelial cells and murine arteries in vivo. Circulation Research. 2008; 103: e1\u2013e9.","DOI":"10.1161\/CIRCRESAHA.108.176883"},{"key":"ref23","doi-asserted-by":"publisher","unstructured":"Kumar S, Kim YR, Vikram A, Naqvi A, Li Q, Kassan M, et al. Sirtuin1-regulated lysine acetylation of p66Shc governs diabetes-induced vascular oxidative stress and endothelial dysfunction. 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Frontiers in Immunology. 2023; 14: 1172892.","DOI":"10.3389\/fimmu.2023.1172892"},{"key":"ref35","doi-asserted-by":"publisher","unstructured":"Mathew DT, Peigh G, Lima JAC, Bielinski SJ, Larson NB, Allison MA, et al. Associations of Circulating Vascular Cell Adhesion Molecule-1 and Intercellular Adhesion Molecule-1 With Long-Term Cardiac Function. Journal of the American Heart Association. 2024; 13: e032213.","DOI":"10.1161\/JAHA.123.032213"},{"key":"ref36","doi-asserted-by":"publisher","unstructured":"Sommer P, Schreinlechner M, Noflatscher M, Lener D, Mair F, Theurl M, et al. Increasing Soluble P-Selectin Levels Predict Higher Peripheral Atherosclerotic Plaque Progression. Journal of Clinical Medicine. 2023; 12: 6430.","DOI":"10.3390\/jcm12206430"},{"key":"ref37","doi-asserted-by":"publisher","unstructured":"Hall IF, Kishta F, Xu Y, Baker AH, Kovacic JC. Endothelial to mesenchymal transition: at the axis of cardiovascular health and disease. Cardiovascular Research. 2024; 120: 223\u2013236.","DOI":"10.1093\/cvr\/cvae021"},{"key":"ref38","doi-asserted-by":"publisher","unstructured":"Mimouni M, Lajoix AD, Desmetz C. Experimental Models to Study Endothelial to Mesenchymal Transition in Myocardial Fibrosis and Cardiovascular Diseases. International Journal of Molecular Sciences. 2023; 25: 382.","DOI":"10.3390\/ijms25010382"},{"key":"ref39","doi-asserted-by":"publisher","unstructured":"Huang Q, Gan Y, Yu Z, Wu H, Zhong Z. Endothelial to Mesenchymal Transition: An Insight in Atherosclerosis. Frontiers in Cardiovascular Medicine. 2021; 8: 734550.","DOI":"10.3389\/fcvm.2021.734550"},{"key":"ref40","doi-asserted-by":"publisher","unstructured":"Liu Q, Liu CQ, Yi WZ, Ouyang PW, Yang BF, Liu Q, et al. Ferroptosis Contributes to Microvascular Dysfunction in Diabetic Retinopathy. The American Journal of Pathology. 2024; 194: 1078\u20131089.","DOI":"10.1016\/j.ajpath.2024.01.019"},{"key":"ref41","doi-asserted-by":"publisher","unstructured":"Zhang H, Lu C, Wu L, Li J, Huang M, Tao X, et al. Exosomes derived from endothelial progenitor cells ameliorate LPS-induced brain microvascular endothelial cells injury by delivering miR-126a-5p. Scientific Reports. 2024; 14: 18469.","DOI":"10.1038\/s41598-024-69163-3"},{"key":"ref42","doi-asserted-by":"publisher","unstructured":"Zhang Y, Yang Q, Cheng H, Zhang Y, Xie Y, Zhang Q. Extracellular vesicles derived from endothelial progenitor cells modified by Houshiheisan promote angiogenesis and attenuate cerebral ischemic injury via miR-126\/PIK3R2. Scientific Reports. 2024; 14: 28166.","DOI":"10.1038\/s41598-024-78717-4"},{"key":"ref43","doi-asserted-by":"publisher","unstructured":"Wilson C, Lee MD, Buckley C, Zhang X, McCarron JG. Mitochondrial ATP Production is Required for Endothelial Cell Control of Vascular Tone. Function (Oxford, England). 2023; 4: zqac063.","DOI":"10.1093\/function\/zqac063"},{"key":"ref44","doi-asserted-by":"publisher","unstructured":"Scheitlin CG, Julian JA, Shanmughapriya S, Madesh M, Tsoukias NM, Alevriadou BR. Endothelial mitochondria regulate the intracellular Ca2+ response to fluid shear stress. American Journal of Physiology. Cell Physiology. 2016; 310: C479\u2013C490.","DOI":"10.1152\/ajpcell.00171.2015"},{"key":"ref45","doi-asserted-by":"publisher","unstructured":"Alzaydi MM, Abdul-Salam VB, Whitwell HJ, Russomanno G, Glynos A, Capece D, et al. Intracellular Chloride Channels Regulate Endothelial Metabolic Reprogramming in Pulmonary Arterial Hypertension. American Journal of Respiratory Cell and Molecular Biology. 2023; 68: 103\u2013115.","DOI":"10.1165\/rcmb.2022-0111OC"},{"key":"ref46","doi-asserted-by":"publisher","unstructured":"Klid S, Algaba-Chueca F, Maym\u00f3-Masip E, Ballesteros M, Ingl\u00e9s M, Guarque A, et al. Impaired angiogenesis in gestational diabetes is linked to succinate\/SUCNR1 axis dysregulation in late gestation. The Journal of Physiology. 2025.  (online ahead of print)","DOI":"10.1113\/JP288010"},{"key":"ref47","doi-asserted-by":"publisher","unstructured":"van Vliet AR, Verfaillie T, Agostinis P. New functions of mitochondria associated membranes in cellular signaling. Biochimica et Biophysica Acta. 2014; 1843: 2253\u20132262.","DOI":"10.1016\/j.bbamcr.2014.03.009"},{"key":"ref48","doi-asserted-by":"crossref","unstructured":"Chen L, Zhang Z, Hoshino A, Zheng HD, Morley M, Arany Z, et al. NADPH production by the oxidative pentose-phosphate pathway supports folate metabolism. Nature Metabolism. 2019; 1: 404\u2013415.","DOI":"10.1038\/s42255-019-0043-x"},{"key":"ref49","doi-asserted-by":"publisher","unstructured":"Citrin KM, Chaube B, Fern\u00e1ndez-Hernando C, Su\u00e1rez Y. Intracellular endothelial cell metabolism in vascular function and dysfunction. Trends in Endocrinology and Metabolism: TEM. 2024; 36: 744\u2013755.","DOI":"10.1016\/j.tem.2024.11.004"},{"key":"ref50","doi-asserted-by":"publisher","unstructured":"Metwally E, Sanchez Solano A, Lavanderos B, Yamasaki E, Thakore P, McClenaghan C, et al. Mitochondrial Ca2+-coupled generation of reactive oxygen species, peroxynitrite formation, and endothelial dysfunction in Cant\u00fa syndrome. JCI Insight. 2024; 9: e176212.","DOI":"10.1172\/jci.insight.176212"},{"key":"ref51","doi-asserted-by":"publisher","unstructured":"Aladaileh SH, Abukhalil MH, Saghir SAM, Hanieh H, Alfwuaires MA, Almaiman AA, et al. Galangin Activates Nrf2 Signaling and Attenuates Oxidative Damage, Inflammation, and Apoptosis in a Rat Model of Cyclophosphamide-Induced Hepatotoxicity. Biomolecules. 2019; 9: 346.","DOI":"10.3390\/biom9080346"},{"key":"ref52","doi-asserted-by":"publisher","unstructured":"Dejana E, Orsenigo F, Lampugnani MG. The role of adherens junctions and VE-cadherin in the control of vascular permeability. Journal of Cell Science. 2008; 121: 2115\u20132122.","DOI":"10.1242\/jcs.017897"},{"key":"ref53","doi-asserted-by":"publisher","unstructured":"Holtermann L, Rivera-Galdos R, Nottebaum AF, Wessel F, Ipe U, Vestweber D. Distinct VE-cadherin serine and tyrosine phosphorylation sites and their role for inflammation-induced vascular permeability in vivo. Cellular and Molecular Life Sciences: CMLS. 2025; 82: 223.","DOI":"10.1007\/s00018-025-05753-2"},{"key":"ref54","doi-asserted-by":"publisher","unstructured":"Manco M, Ammirata G, Petrillo S, De Giorgio F, Fontana S, Riganti C, et al. FLVCR1a Controls Cellular Cholesterol Levels through the Regulation of Heme Biosynthesis and Tricarboxylic Acid Cycle Flux in Endothelial Cells. Biomolecules. 2024; 14: 149.","DOI":"10.3390\/biom14020149"},{"key":"ref55","doi-asserted-by":"publisher","unstructured":"Culley MK, Rao RJ, Mehta M, Zhao J, El Khoury W, Harvey LD, et al. Frataxin deficiency disrupts mitochondrial respiration and pulmonary endothelial cell function. Vascular Pharmacology. 2023; 151: 107181.","DOI":"10.1016\/j.vph.2023.107181"},{"key":"ref56","doi-asserted-by":"publisher","unstructured":"Zhang Y, Li C, Pei Y, Zheng L, Sun X, Zhao Z, et al. Trelagliptin ameliorates oxygen-glucose deprivation\/reperfusion (OGD\/R)-induced mitochondrial dysfunction and metabolic disturbance of endothelial cells. Human Cell. 2021; 34: 1717\u20131726.","DOI":"10.1007\/s13577-021-00594-0"},{"key":"ref57","doi-asserted-by":"publisher","unstructured":"Titus AS, Sung EA, Zablocki D, Sadoshima J. Mitophagy for cardioprotection. Basic Research in Cardiology. 2023; 118: 42.","DOI":"10.1007\/s00395-023-01009-x"},{"key":"ref58","doi-asserted-by":"publisher","unstructured":"Head B, Griparic L, Amiri M, Gandre-Babbe S, van der Bliek AM. Inducible proteolytic inactivation of OPA1 mediated by the OMA1 protease in mammalian cells. The Journal of Cell Biology. 2009; 187: 959\u2013966.","DOI":"10.1083\/jcb.200906083"},{"key":"ref59","doi-asserted-by":"publisher","unstructured":"Wu W, Xu H, Wang Z, Mao Y, Yuan L, Luo W, et al. PINK1-Parkin-Mediated Mitophagy Protects Mitochondrial Integrity and Prevents Metabolic Stress-Induced Endothelial Injury. PloS One. 2015; 10: e0132499.","DOI":"10.1371\/journal.pone.0132499"},{"key":"ref60","doi-asserted-by":"publisher","unstructured":"Liu W, Song H, Xu J, Guo Y, Zhang C, Yao Y, et al. Low shear stress inhibits endothelial mitophagy via caveolin-1\/miR-7-5p\/SQSTM1 signaling pathway. Atherosclerosis. 2022; 356: 9\u201317.","DOI":"10.1016\/j.atherosclerosis.2022.07.014"},{"key":"ref61","doi-asserted-by":"publisher","unstructured":"Ashar FN, Zhang Y, Longchamps RJ, Lane J, Moes A, Grove ML, et al. Association of Mitochondrial DNA Copy Number With Cardiovascular Disease. JAMA Cardiology. 2017; 2: 1247\u20131255.","DOI":"10.1001\/jamacardio.2017.3683"},{"key":"ref62","doi-asserted-by":"publisher","unstructured":"Uffelmann E, Huang QQ, Munung NS, De Vries J, Okada Y, Martin AR, et al. Genome-wide association studies. Nature Reviews Methods Primers. 2021; 1: 59.","DOI":"10.1038\/s43586-021-00056-9"},{"key":"ref63","doi-asserted-by":"publisher","unstructured":"Liu X, Sun X, Zhang Y, Jiang W, Lai M, Wiggins KL, et al. Association Between Whole Blood-Derived Mitochondrial DNA Copy Number, Low-Density Lipoprotein Cholesterol, and Cardiovascular Disease Risk. Journal of the American Heart Association. 2023; 12: e029090.","DOI":"10.1161\/JAHA.122.029090"},{"key":"ref64","doi-asserted-by":"publisher","unstructured":"Wang Z, Li Z, Liu H, Yang C, Li X. Mitochondrial clonal mosaicism encodes a biphasic molecular clock of aging. Nature Aging. 2025; 5: 1637\u20131651.","DOI":"10.1038\/s43587-025-00890-6"},{"key":"ref65","doi-asserted-by":"publisher","unstructured":"Xiao Y, Jin W, Ju L, Fu J, Wang G, Yu M, et al. Tracking single-cell evolution using clock-like chromatin accessibility loci. Nature Biotechnology. 2024; 43: 784\u2013798.","DOI":"10.1038\/s41587-024-02241-z"},{"key":"ref66","doi-asserted-by":"publisher","unstructured":"Sriram K, Qi Z, Yuan D, Malhi NK, Liu X, Calandrelli R, et al. Regulation of nuclear transcription by mitochondrial RNA in endothelial cells. eLife. 2024; 13: e86204.","DOI":"10.7554\/eLife.86204"},{"key":"ref67","doi-asserted-by":"publisher","unstructured":"Cai Y, Li L, Shao C, Chen Y, Wang Z. Therapeutic Strategies for Angiogenesis Based on Endothelial Cell Epigenetics. Journal of Cardiovascular Translational Research. 2024; 17: 816\u2013827.","DOI":"10.1007\/s12265-024-10485-y"},{"key":"ref68","doi-asserted-by":"publisher","unstructured":"Maurya MR, Gupta S, Li JYS, Ajami NE, Chen ZB, Shyy JYJ, et al. Longitudinal shear stress response in human endothelial cells to atheroprone and atheroprotective conditions. Proceedings of the National Academy of Sciences of the United States of America. 2021; 118: e2023236118.","DOI":"10.1073\/pnas.2023236118"},{"key":"ref69","doi-asserted-by":"publisher","unstructured":"Andueza A, Kumar S, Kim J, Kang DW, Mumme HL, Perez JI, et al. Endothelial Reprogramming by Disturbed Flow Revealed by Single-Cell RNA and Chromatin Accessibility Study. Cell Reports. 2020; 33: 108491.","DOI":"10.1016\/j.celrep.2020.108491"},{"key":"ref70","doi-asserted-by":"publisher","unstructured":"Zaeifi D, Jamialahmadi K, Karimi G. The Role of p66Shc in Cancer: Molecular Mechanisms and Therapeutic Implications. Journal of Cellular and Molecular Medicine. 2025; 29: e70737.","DOI":"10.1111\/jcmm.70737"},{"key":"ref71","doi-asserted-by":"publisher","unstructured":"Bochaton T, Crola-Da-Silva C, Pillot B, Villedieu C, Ferreras L, Alam MR, et al. Inhibition of myocardial reperfusion injury by ischemic postconditioning requires sirtuin 3-mediated deacetylation of cyclophilin D. Journal of Molecular and Cellular Cardiology. 2015; 84: 61\u201369.","DOI":"10.1016\/j.yjmcc.2015.03.017"},{"key":"ref72","doi-asserted-by":"publisher","unstructured":"Yin MT, Guo L. Mitochondrial DNA methylation: State-of-the-art in molecular mechanisms and disease implications. Journal of Advanced Research. 2025.  (online ahead of print)","DOI":"10.1016\/j.jare.2025.08.029"},{"key":"ref73","doi-asserted-by":"publisher","unstructured":"Csiszar A, Tarantini S, Yabluchanskiy A, Balasubramanian P, Kiss T, Farkas E, et al. Role of endothelial NAD+ deficiency in age-related vascular dysfunction. American Journal of Physiology. Heart and Circulatory Physiology. 2019; 316: H1253\u2013H1266.","DOI":"10.1152\/ajpheart.00039.2019"},{"key":"ref74","doi-asserted-by":"publisher","unstructured":"Ngamratanapaiboon S, Yambangyang P. Quantification of antipsychotic biotransformation in brain microvascular endothelial cells by using untargeted metabolomics. Drug Discoveries & Therapeutics. 2021; 15: 317\u2013324.","DOI":"10.5582\/ddt.2021.01101"},{"key":"ref75","doi-asserted-by":"publisher","unstructured":"Li S, Wang F, Sun D. The renal microcirculation in chronic kidney disease: novel diagnostic methods and therapeutic perspectives. Cell & Bioscience. 2021; 11: 90.","DOI":"10.1186\/s13578-021-00606-4"},{"key":"ref76","doi-asserted-by":"publisher","unstructured":"Jamal M, Masood A, Belcastro R, Lopez L, Li J, Belik J, et al. Lipid hydroperoxide formation regulates postnatal rat lung cell apoptosis and alveologenesis. Free Radical Biology & Medicine. 2013; 55: 83\u201392.","DOI":"10.1016\/j.freeradbiomed.2012.11.012"},{"key":"ref77","doi-asserted-by":"publisher","unstructured":"Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. The New England Journal of Medicine. 2015; 373: 2117\u20132128.","DOI":"10.1056\/NEJMoa1504720"},{"key":"ref78","doi-asserted-by":"publisher","unstructured":"Chen B, Guo J, Ye H, Wang X, Feng Y. Role and molecular mechanisms of SGLT2 inhibitors in pathological cardiac remodeling (Review). Molecular Medicine Reports. 2024; 29: 73.","DOI":"10.3892\/mmr.2024.13197"},{"key":"ref79","doi-asserted-by":"publisher","unstructured":"Ferhatbegovi\u0107 L, Mr\u0161i\u0107 D, Maci\u0107-D\u017eankovi\u0107 A. The benefits of GLP1 receptors in cardiovascular diseases. Frontiers in Clinical Diabetes and Healthcare. 2023; 4: 1293926.","DOI":"10.3389\/fcdhc.2023.1293926"},{"key":"ref80","doi-asserted-by":"publisher","unstructured":"Rivera FB, Cruz LLA, Magalong JV, Ruyeras JMMJ, Aparece JP, Bantayan NRB, et al. Cardiovascular and renal outcomes of glucagon-like peptide 1 receptor agonists among patients with and without type 2 diabetes mellitus: A meta-analysis of randomized placebo-controlled trials. American Journal of Preventive Cardiology. 2024; 18: 100679.","DOI":"10.1016\/j.ajpc.2024.100679"},{"key":"ref81","doi-asserted-by":"publisher","unstructured":"Siddiqui MR, Reddy NM, Faridi HM, Shahid M, Shanley TP. Metformin alleviates lung-endothelial hyperpermeability by regulating cofilin-1\/PP2AC pathway. Frontiers in Pharmacology. 2023; 14: 1211460.","DOI":"10.3389\/fphar.2023.1211460"},{"key":"ref82","doi-asserted-by":"publisher","unstructured":"Kim HS, Ren G, Kim T, Bhatnagar S, Yang Q, Bahk YY, et al. Metformin reduces saturated fatty acid-induced lipid accumulation and inflammatory response by restoration of autophagic flux in endothelial cells. Scientific Reports. 2020; 10: 13523.","DOI":"10.1038\/s41598-020-70347-w"},{"key":"ref83","doi-asserted-by":"publisher","unstructured":"Wang F, Yan Y, Wang D, Fan Q, Yi F, Yang X, et al. Effects of Metformin on CIMT and FMD in PCOS patients: a systematic review and meta-analysis. BMC Women\u2019s Health. 2024; 24: 426.","DOI":"10.1186\/s12905-024-03275-w"},{"key":"ref84","doi-asserted-by":"publisher","unstructured":"Natali A, Ferrannini E. Endothelial dysfunction in type 2 diabetes. Diabetologia. 2012; 55: 1559\u20131563.","DOI":"10.1007\/s00125-011-2445-5"},{"key":"ref85","doi-asserted-by":"publisher","unstructured":"Whitson JA, Mart\u00edn-P\u00e9rez M, Zhang T, Gaffrey MJ, Merrihew GE, Huang E, et al. Elamipretide (SS-31) treatment attenuates age-associated post-translational modifications of heart proteins. GeroScience. 2021; 43: 2395\u20132412.","DOI":"10.1007\/s11357-021-00447-6"},{"key":"ref86","doi-asserted-by":"publisher","unstructured":"McDermott MM, Martens CR, Domanchuk KJ, Zhang D, Peek CB, Criqui MH, et al. Nicotinamide riboside for peripheral artery disease: the NICE randomized clinical trial. Nature Communications. 2024; 15: 5046.","DOI":"10.1038\/s41467-024-49092-5"},{"key":"ref87","doi-asserted-by":"publisher","unstructured":"Szarvas Z, Reyff ZA, Peterfi A, Pinto CB, Owens CD, Kaposzta Z, et al. Effects of NAD+ supplementation with oral nicotinamide riboside on vascular health and cognitive function in older adults with peripheral artery disease: Results from a pilot 4-week open-label clinical trial. The Journal of Pharmacology and Experimental Therapeutics. 2025; 392: 103607.","DOI":"10.1016\/j.jpet.2025.103607"},{"key":"ref88","doi-asserted-by":"publisher","unstructured":"Pizzamiglio C, Stefanetti RJ, McFarland R, Thomas N, Ransley G, Hugerth M, et al. Optimizing rare disorder trials: a phase 1a\/1b randomized study of KL1333 in adults with mitochondrial disease. Brain: a Journal of Neurology. 2025; 148: 39\u201346.","DOI":"10.1093\/brain\/awae308"},{"key":"ref89","doi-asserted-by":"publisher","unstructured":"Pinaffi-Langley AC, Pinto CB, Szarvas Z, Peterfi A, Kaposzta Z, Mukli P, et al. Urolithin A supplementation to improve endothelial and cerebrovascular function in middle-aged adults with obesity: Study protocol for a double-blind placebo-controlled randomized study. Clinical Nutrition Open Science. 2025; 61: 217\u2013230.","DOI":"10.1016\/j.nutos.2025.04.004"},{"key":"ref90","doi-asserted-by":"publisher","unstructured":"Ryu D, Mouchiroud L, Andreux PA, Katsyuba E, Moullan N, Nicolet-Dit-F\u00e9lix AA, et al. Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents. Nature Medicine. 2016; 22: 879\u2013888.","DOI":"10.1038\/nm.4132"},{"key":"ref91","doi-asserted-by":"publisher","unstructured":"Hu S, Gao Y, Gao R, Wang Y, Qu Y, Yang J, et al. The selective STING inhibitor H-151 preserves myocardial function and ameliorates cardiac fibrosis in murine myocardial infarction. International Immunopharmacology. 2022; 107: 108658.","DOI":"10.1016\/j.intimp.2022.108658"},{"key":"ref92","doi-asserted-by":"publisher","unstructured":"An C, Sun F, Liu C, Huang S, Xu T, Zhang C, et al. IQGAP1 promotes mitochondrial damage and activation of the mtDNA sensor cGAS-STING pathway to induce endothelial cell pyroptosis leading to atherosclerosis. International Immunopharmacology. 2023; 123: 110795.","DOI":"10.1016\/j.intimp.2023.110795"},{"key":"ref93","doi-asserted-by":"publisher","unstructured":"Lin RZ, Im GB, Luo AC, Zhu Y, Hong X, Neumeyer J, et al. Mitochondrial transfer mediates endothelial cell engraftment through mitophagy. Nature. 2024; 629: 660\u2013668.","DOI":"10.1038\/s41586-024-07340-0"},{"key":"ref94","doi-asserted-by":"publisher","unstructured":"Yamada Y, Furukawa R, Yasuzaki Y, Harashima H. Dual function MITO-Porter, a nano carrier integrating both efficient cytoplasmic delivery and mitochondrial macromolecule delivery. Molecular Therapy: the Journal of the American Society of Gene Therapy. 2011; 19: 1449\u20131456.","DOI":"10.1038\/mt.2011.99"},{"key":"ref95","doi-asserted-by":"publisher","unstructured":"Hu Z, Sim Y, Kon OL, Ng WH, Ribeiro AJM, Ramos MJ, et al. Unique Triphenylphosphonium Derivatives for Enhanced Mitochondrial Uptake and Photodynamic Therapy. Bioconjugate Chemistry. 2017; 28: 590\u2013599.","DOI":"10.1021\/acs.bioconjchem.6b00682"},{"key":"ref96","doi-asserted-by":"publisher","unstructured":"Liu Y, Lyons CJ, Ayu C, O\u2019Brien T. Recent advances in endothelial colony-forming cells: from the transcriptomic perspective. Journal of Translational Medicine. 2024; 22: 313.","DOI":"10.1186\/s12967-024-05108-8"},{"key":"ref97","doi-asserted-by":"publisher","unstructured":"Rossman MJ, Santos-Parker JR, Steward CAC, Bispham NZ, Cuevas LM, Rosenberg HL, et al. Chronic Supplementation With a Mitochondrial Antioxidant (MitoQ) Improves Vascular Function in Healthy Older Adults. Hypertension (Dallas, Tex.: 1979). 2018; 71: 1056\u20131063.","DOI":"10.1161\/HYPERTENSIONAHA.117.10787"},{"key":"ref98","doi-asserted-by":"publisher","unstructured":"Polhemus DJ, Li Z, Pattillo CB, Gojon G, Sr, Gojon G, Jr, Giordano T, et al. A novel hydrogen sulfide prodrug, SG1002, promotes hydrogen sulfide and nitric oxide bioavailability in heart failure patients. Cardiovascular Therapeutics. 2015; 33: 216\u2013226.","DOI":"10.1111\/1755-5922.12128"},{"key":"ref99","doi-asserted-by":"publisher","unstructured":"S\u00e1nchez-Fern\u00e1ndez A, Skouras DB, Dinarello CA, L\u00f3pez-Vales R. OLT1177 (Dapansutrile), a Selective NLRP3 Inflammasome Inhibitor, Ameliorates Experimental Autoimmune Encephalomyelitis Pathogenesis. Frontiers in Immunology. 2019; 10: 2578.","DOI":"10.3389\/fimmu.2019.02578"},{"key":"ref100","doi-asserted-by":"publisher","unstructured":"Krolak T, Chan KY, Kaplan L, Huang Q, Wu J, Zheng Q, et al. A High-Efficiency AAV for Endothelial Cell Transduction Throughout the Central Nervous System. Nature Cardiovascular Research. 2022; 1: 389\u2013400.","DOI":"10.1038\/s44161-022-00046-4"},{"key":"ref101","doi-asserted-by":"publisher","unstructured":"Chen X, Wolfe DA, Bindu DS, Zhang M, Taskin N, Goertsen D, et al. Functional gene delivery to and across brain vasculature of systemic AAVs with endothelial-specific tropism in rodents and broad tropism in primates. Nature Communications. 2023; 14: 3345.","DOI":"10.1038\/s41467-023-38582-7"},{"key":"ref102","doi-asserted-by":"publisher","unstructured":"Wang X, He B. Insight into endothelial cell-derived extracellular vesicles in cardiovascular disease: Molecular mechanisms and clinical implications. Pharmacological Research. 2024; 207: 107309.","DOI":"10.1016\/j.phrs.2024.107309"},{"key":"ref103","doi-asserted-by":"publisher","unstructured":"Velazquez-Rivera E, Dey O, Kim NS, Cao W, Ye Q, Gao P, et al. Specific targeting of brain endothelial cells using enhancer AAV vectors. Neuron. 2025; 113: 1562\u20131578.e6.","DOI":"10.1016\/j.neuron.2025.03.031"},{"key":"ref104","doi-asserted-by":"publisher","unstructured":"Jimenez-Trinidad FR, Calvo-Gomez S, Sabat\u00e9 M, Brugaletta S, Campuzano V, Egea G, et al. Extracellular vesicles as mediators of endothelial dysfunction in cardiovascular diseases. International Journal of Molecular Sciences. 2025; 26: 1008.","DOI":"10.3390\/ijms26031008"},{"key":"ref105","doi-asserted-by":"publisher","unstructured":"Atkin-Smith GK, Santavanond JP, Light A, Rimes JS, Samson AL, Er J, et al. In situ visualization of endothelial cell-derived extracellular vesicle formation in steady state and malignant conditions. Nature Communications. 2024; 15: 8802.","DOI":"10.1038\/s41467-024-52867-5"},{"key":"ref106","doi-asserted-by":"publisher","unstructured":"Allison SJ. Chronic kidney disease: Serious adverse effects associated with IV iron in CKD. Nature Reviews. Nephrology. 2015; 11: 506.","DOI":"10.1038\/nrneph.2015.112"},{"key":"ref107","doi-asserted-by":"publisher","unstructured":"Cheruku GR, Wilson CV, Raviendran S, Xiao Q. Recent advances and future perspectives in vascular organoids and vessel-on-chip. Organoids. 2024; 3: 203\u2013246.","DOI":"10.3390\/organoids3030014"},{"key":"ref108","doi-asserted-by":"publisher","unstructured":"Lewis-Israeli YR, Wasserman AH, Gabalski MA, Volmert BD, Ming Y, Ball KA, et al. Self-assembling human heart organoids for the modeling of cardiac development and congenital heart disease. 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