{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T23:09:54Z","timestamp":1793747394379,"version":"4.6.1"},"reference-count":126,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,4,7]],"date-time":"2022-04-07T00:00:00Z","timestamp":1649289600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82070396, 81974032"],"award-info":[{"award-number":["82070396, 81974032"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:p>The cardiovascular complications contribute to a majority of diabetes associated morbidity and mortality, accounting for 44% of death in those patients with type 1 diabetes mellitus (DM) and 52% of deaths in type 2 DM. Diabetes elicits cardiovascular dysfunction through 2 major mechanisms: ischemic and non-ischemic. Non-ischemic injury is usually under-recognized although common in DM patients, and also a pathogenic factor of heart failure in those diabetic individuals complicated with ischemic heart disease. Diabetic cardiomyopathy (DCM) is defined as a heart disease in which the myocardium is structurally and functionally abnormal in the absence of coronary artery disease, hypertensive, valvular, or congenital heart disorders in diabetic patients, theoretically caused by non-ischemic injury solely. Current therapeutic strategies targeting DCM mainly address the increased blood glucose levels, however, the effects on heart function are disappointed. Accumulating data indicate endothelial dysfunction plays a critical role in the initiation and development of DCM. Hyperglycemia, hyperinsulinemia, and insulin resistance cause the damages of endothelial function, including barrier dysfunction, impaired nitric oxide (NO) activity, excessive reactive oxygen species (ROS) production, oxidative stress, and inflammatory dysregulation. In turn, endothelial dysfunction promotes impaired myocardial metabolism, intracellular Ca<jats:sup>2+<\/jats:sup> mishandling, endoplasmic reticulum (ER) stress, mitochondrial defect, accumulation of advanced glycation end products, and extracellular matrix (ECM) deposit, leads to cardiac stiffness, fibrosis, and remodeling, eventually results in cardiac diastolic dysfunction, systolic dysfunction, and heart failure. While endothelial dysfunction is closely related to cardiac dysfunction and heart failure seen in DCM, clinical strategies for restoring endothelial function are still missing. This review summarizes the timely findings related to the effects of endothelial dysfunction on the disorder of myocardium as well as cardiac function, provides mechanical insights in pathogenesis and pathophysiology of DCM developing, and highlights potential therapeutic targets.<\/jats:p>","DOI":"10.3389\/fendo.2022.851941","type":"journal-article","created":{"date-parts":[[2022,4,7]],"date-time":"2022-04-07T04:40:52Z","timestamp":1649306452000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":168,"title":["Endothelial Dysfunction and Diabetic Cardiomyopathy"],"prefix":"10.3389","volume":"13","author":[{"given":"Moran","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongsheng","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheng","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiagao","family":"Lv","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,4,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"107843","DOI":"10.1016\/j.diabres.2019.107843","article-title":"Global and Regional Diabetes Prevalence Estimates for 2019 and Projections for 2030 and 2045: Results From the International Diabetes Federation Diabetes Atlas, 9 Edition","volume":"157","author":"Saeedi","year":"2019","journal-title":"Diabetes Res Clin Pract"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1161\/01.HYP.37.4.1053","article-title":"Diabetes, Hypertension, and Cardiovascular Disease: An Update","volume":"37","author":"Sowers","year":"2001","journal-title":"Hypertension (Dallas Tex 1979)"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0802743","article-title":"Effects of Intensive Glucose Lowering in Type 2 Diabetes","volume":"358","author":"Gerstein","year":"2008","journal-title":"N Engl J Med"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0802987","article-title":"Intensive Blood Glucose Control and Vascular Outcomes in Patients With Type 2 Diabetes","volume":"358","author":"Patel","year":"2008","journal-title":"N Engl J Med"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1136\/heart.85.3.247","article-title":"Diabetic Cardiomyopathy: Fact or Fiction","volume":"85","author":"Francis","year":"2001","journal-title":"Heart"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/S0735-1097(03)00647-8","article-title":"Diabetic Cardiomyopathy","volume":"42","author":"Picano","year":"2003","journal-title":"Importance Being Earliest J Am Coll Cardiol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00278.2006","article-title":"Role of Changes in Cardiac Metabolism in Development of Diabetic Cardiomyopathy","volume":"291","author":"An","year":"2006","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.117.311586","article-title":"Diabetic Cardiomyopathy: An Update of Mechanisms Contributing to This Clinical Entity","volume":"122","author":"Jia","year":"2018","journal-title":"Circ Res"},{"key":"B9","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1007\/BF00569929","article-title":"The Role of Endothelium in the Pathogenesis of Diabetic Microangiopathy","volume":"30","author":"La Selva","year":"1993","journal-title":"Acta Diabetol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1139\/y03-053","article-title":"Endothelins in Chronic Diabetic Complications","volume":"81","author":"Khan","year":"2003","journal-title":"Can J Physiol Pharmacol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1038\/nrendo.2015.216","article-title":"Insulin Resistance and Hyperinsulinaemia in Diabetic Cardiomyopathy","volume":"12","author":"Jia","year":"2016","journal-title":"Nat Rev Endocrinol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1136\/pgmj.2007.064048","article-title":"Cardiac Autonomic Neuropathy in Diabetes Mellitus: Prevalence, Risk Factors and Utility of Corrected QT Interval in the ECG for its Diagnosis","volume":"84","author":"Pappachan","year":"2008","journal-title":"Postgrad Med J"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00663.2007","article-title":"Expression of SERCA Isoform With Faster Ca2+ Transport Properties Improves Postischemic Cardiac Function and Ca2+ Handling and Decreases Myocardial Infarction","volume":"293","author":"Talukder","year":"2007","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199309303291401","article-title":"The Effect of Intensive Treatment of Diabetes on the Development and Progression of Long-Term Complications in Insulin-Dependent Diabetes Mellitus","volume":"329","author":"Nathan","year":"1993","journal-title":"N Engl J Med"},{"key":"B15","first-page":"74","article-title":"Endothelial Dysfunction in Diabetes Mellitus: Role in Cardiovascular Disease","volume":"1","author":"Feener","year":"2001","journal-title":"Heart Fail Monit"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.94.6.1276","article-title":"Chronic Hyperglycemia Impairs Endothelial Function and Insulin Sensitivity via Different Mechanisms in Insulin-Dependent Diabetes Mellitus","volume":"94","author":"M\u00e4kimattila","year":"1996","journal-title":"Circulation"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.2000.279.1.E11","article-title":"Effects of Simulated Hyperglycemia, Insulin, and Glucagon on Endothelial Nitric Oxide Synthase Expression","volume":"279","author":"Ding","year":"2000","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1111\/1753-0407.12521","article-title":"Macro- and Microvascular Endothelial Dysfunction in Diabetes","volume":"9","author":"Shi","year":"2017","journal-title":"J Diabetes"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvr233","article-title":"Endothelial Nitric Oxide Synthase Enhancer Reduces Oxidative Stress and Restores Endothelial Function in Db\/Db Mice","volume":"92","author":"Cheang","year":"2011","journal-title":"Cardiovasc Res"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9343(83)90257-7","article-title":"Increased Capillary Permeability in Diabetes Mellitus and its Relationship to Microvascular Angiopathy","volume":"75","author":"Viberti","year":"1983","journal-title":"Am J Med"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.81.3.363","article-title":"High Glucose Concentrations Increase Endothelial Cell Permeability via Activation of Protein Kinase C Alpha","volume":"81","author":"Hempel","year":"1997","journal-title":"Circ Res"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.87.5.412","article-title":"Protein Kinase C Activation Contributes to Microvascular Barrier Dysfunction in the Heart at Early Stages of Diabetes","volume":"87","author":"Yuan","year":"2000","journal-title":"Circ Res"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1126\/science.272.5262.728","article-title":"Amelioration of Vascular Dysfunctions in Diabetic Rats by an Oral PKC Beta Inhibitor","volume":"272","author":"Ishii","year":"1996","journal-title":"Sci (New York NY)"},{"key":"B24","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1186\/1475-2840-13-105","article-title":"Disruption of Endothelial Adherens Junctions by High Glucose Is Mediated by Protein Kinase C-\u03b2-Dependent Vascular Endothelial Cadherin Tyrosine Phosphorylation","volume":"13","author":"Haidari","year":"2014","journal-title":"Cardiovasc Diabetol"},{"key":"B25","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1007\/s00702-010-0484-6","article-title":"New Aspects of the Molecular Constituents of Tissue Barriers","volume":"118","author":"Bauer","year":"2011","journal-title":"J Neural Transm (Vienna)"},{"key":"B26","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1016\/j.redox.2015.03.005","article-title":"High Glucose, Glucose Fluctuation and Carbonyl Stress Enhance Brain Microvascular Endothelial Barrier Dysfunction: Implications for Diabetic Cerebral Microvasculature","volume":"5","author":"Li","year":"2015","journal-title":"Redox Biol"},{"key":"B27","doi-asserted-by":"publisher","first-page":"718","DOI":"10.3390\/antiox10050718","article-title":"Reactive Oxygen Species-Induced TRPM2-Mediated Ca(2+) Signalling in Endothelial Cells","volume":"10","author":"Ding","year":"2021","journal-title":"Antioxid (Basel)"},{"key":"B28","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/j.niox.2014.08.004","article-title":"Nitric Oxide Synthases and Diabetic Cardiomyopathy","volume":"43","author":"Khanna","year":"2014","journal-title":"Nitric Oxide"},{"key":"B29","article-title":"Endothelial Nitric Oxide Synthase (eNOS) Expression and Localization in Healthy and Diabetic Rat Hearts","volume":"31","author":"Felaco","year":"2001","journal-title":"Ann Clin Lab Sci"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1378\/chest.122.4.1412","article-title":"Hypertension Plus Diabetes Mimics the Cardiomyopathy Induced by Nitric Oxide Inhibition in Rats","volume":"122","author":"Sampaio","year":"2002","journal-title":"Chest"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00713.2007","article-title":"IGF-I Alleviates Diabetes-Induced RhoA Activation, eNOS Uncoupling, and Myocardial Dysfunction","volume":"294","author":"Ren","year":"2008","journal-title":"Am J Physiol Regul Integr Comp Physiol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1111\/j.1463-1326.2011.01369.x","article-title":"Inhibition of NADPH Oxidase Alleviates Experimental Diabetes-Induced Myocardial Contractile Dysfunction","volume":"13","author":"Roe","year":"2011","journal-title":"Diabetes Obes Metab"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.15.1.323","article-title":"Nitric Oxide and Macrophage Function","volume":"15","author":"MacMicking","year":"1997","journal-title":"Annu Rev Immunol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00591.2005","article-title":"Increased Expression of iNOS is Associated With Endothelial Dysfunction and Impaired Pressor Responsiveness in Streptozotocin-Induced Diabetes","volume":"289","author":"Nagareddy","year":"2005","journal-title":"Am J Physiol Heart Circulatory Physiol"},{"key":"B35","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1186\/1743-7075-3-27","article-title":"Differential Effects of Curcumin on Vasoactive Factors in the Diabetic Rat Heart","volume":"3","author":"Farhangkhoee","year":"2006","journal-title":"Nutr Metab (Lond)"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.3181\/00379727-231-2310925","article-title":"Effects of a Selective Endothelin a Receptor Antagonist on the Expressions of iNOS and eNOS in the Heart of Early Streptozotocin-Induced Diabetic Rats","volume":"231","author":"Jesmin","year":"2006","journal-title":"Exp Biol Med (Maywood NJ)"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2012.08.013","article-title":"Diabetes Triggers a PARP1 Mediated Death Pathway in the Heart Through Participation of Foxo1","volume":"53","author":"Puthanveetil","year":"2012","journal-title":"J Mol Cell Cardiol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1111\/j.1440-1681.2011.05535.x","article-title":"Inhibition of Nitric Oxide Synthase Uncoupling by Sepiapterin Improves Left Ventricular Function in Streptozotocin-Induced Diabetic Mice","volume":"38","author":"Jo","year":"2011","journal-title":"Clin Exp Pharmacol Physiol"},{"key":"B39","article-title":"Evidence for Inducible Nitric-Oxide Synthase Expression and Activity in Vascular Smooth Muscle of Streptozotocin-Diabetic Rats","volume":"296","author":"Bardell","year":"2001","journal-title":"J Pharmacol Exp Ther"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.niox.2006.12.001","article-title":"Reduced Neuronal Nitric Oxide Synthase Expression Contributes to Cardiac Oxidative Stress and Nitroso-Redox Imbalance in Ob\/Ob Mice","volume":"16","author":"Saraiva","year":"2007","journal-title":"Nitric Oxide"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9149(01)02063-X","article-title":"Plasma Concentrations of Asymmetric Dimethylarginine are Increased in Patients With Type 2 Diabetes Mellitus","volume":"88","author":"Abbasi","year":"2001","journal-title":"Am J Cardiol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1097\/00005344-200308000-00006","article-title":"Elevated Levels of the Serum Endogenous Inhibitor of Nitric Oxide Synthase and Metabolic Control in Rats With Streptozotocin-Induced Diabetes","volume":"42","author":"Xiong","year":"2003","journal-title":"J Cardiovasc Pharmacol"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1172\/JCI115014","article-title":"Advanced Glycosylation Products Quench Nitric Oxide and Mediate Defective Endothelium-Dependent Vasodilatation in Experimental Diabetes","volume":"87","author":"Bucala","year":"1991","journal-title":"J Clin Invest"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000162472.52990.36","article-title":"Progressive Attenuation of Myocardial Vascular Endothelial Growth Factor Expression Is a Seminal Event in Diabetic Cardiomyopathy: Restoration of Microvascular Homeostasis and Recovery of Cardiac Function in Diabetic Cardiomyopathy After Replenishment of Local Vascular Endothelial Growth Factor","volume":"111","author":"Yoon","year":"2005","journal-title":"Circulation"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2003.09.007","article-title":"Heme Oxygenase in Diabetes-Induced Oxidative Stress in the Heart","volume":"35","author":"Farhangkhoee","year":"2003","journal-title":"J Mol Cell Cardiol"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1038\/414813a","article-title":"Biochemistry and Molecular Cell Biology of Diabetic Complications","volume":"414","author":"Brownlee","year":"2001","journal-title":"Nature"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1038\/35008121","article-title":"Normalizing Mitochondrial Superoxide Production Blocks Three Pathways of Hyperglycaemic Damage","volume":"404","author":"Nishikawa","year":"2000","journal-title":"Nature"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000093660.86242.BB","article-title":"Oxidative Stress and Cardiovascular Injury: Part I: Basic Mechanisms and In Vivo Monitoring of ROS","volume":"108","author":"Griendling","year":"2003","journal-title":"Circulation"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.88.2.e14","article-title":"Mechanisms Underlying Endothelial Dysfunction in Diabetes Mellitus","volume":"88","author":"Hink","year":"2001","journal-title":"Circ Res"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1172\/JCI0214442","article-title":"Oxidation of the Zinc-Thiolate Complex and Uncoupling of Endothelial Nitric Oxide Synthase by Peroxynitrite","volume":"109","author":"Zou","year":"2002","journal-title":"J Clin Invest"},{"key":"B51","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1111\/bcpt.12402","article-title":"Antidiabetic Agents and Endothelial Dysfunction - Beyond Glucose Control","volume":"117","author":"Eriksson","year":"2015","journal-title":"Basic Clin Pharmacol Toxicol"},{"key":"B52","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1186\/1475-2840-12-142","article-title":"Hyperglycemia Induces Differential Change in Oxidative Stress at Gene Expression and Functional Levels in HUVEC and HMVEC","volume":"12","author":"Patel","year":"2013","journal-title":"Cardiovasc Diabetol"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1172\/JCI18127","article-title":"Inhibition of GAPDH Activity by Poly(ADP-Ribose) Polymerase Activates Three Major Pathways of Hyperglycemic Damage in Endothelial Cells","volume":"112","author":"Du","year":"2003","journal-title":"J Clin Invest"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1038\/83241","article-title":"Diabetic Endothelial Dysfunction: The Role of Poly(ADP-Ribose) Polymerase Activation","volume":"7","author":"Garcia Soriano","year":"2001","journal-title":"Nat Med"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.3892\/ijmm.2015.2100","article-title":"Role of Sphingosine-1-Phosphate Receptor 1 and Sphingosine-1-Phosphate Receptor 2 in Hyperglycemia-Induced Endothelial Cell Dysfunction","volume":"35","author":"Chen","year":"2015","journal-title":"Int J Mol Med"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.55.01.06.db05-0943","article-title":"Activation of AMP-Activated Protein Kinase Reduces Hyperglycemia-Induced Mitochondrial Reactive Oxygen Species Production and Promotes Mitochondrial Biogenesis in Human Umbilical Vein Endothelial Cells","volume":"55","author":"Kukidome","year":"2006","journal-title":"Diabetes"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexmp.2018.01.008","article-title":"Potential of Anti-Inflammatory Agents for Treatment of Atherosclerosis","volume":"104","author":"Chistiakov","year":"2018","journal-title":"Exp Mol Pathol"},{"key":"B58","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1016\/j.atherosclerosis.2020.06.016","article-title":"Hyperinsulinemia Promotes Endothelial Inflammation via Increased Expression and Release of Angiopoietin-2","volume":"307","author":"Chandel","year":"2020","journal-title":"Atherosclerosis"},{"key":"B59","doi-asserted-by":"publisher","first-page":"6375","DOI":"10.3390\/ijms22126375","article-title":"Endothelial Progenitor Cell-Derived Extracellular Vesicles: Potential Therapeutic Application in Tissue Repair and Regeneration","volume":"22","author":"Terriaca","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1001\/jama.288.20.2579","article-title":"Molecular Understanding of Hyperglycemia\u2019s Adverse Effects for Diabetic Complications","volume":"288","author":"Sheetz","year":"2002","journal-title":"JAMA"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1007\/BF00429099","article-title":"Impaired Endothelium-Dependent and Independent Vasodilation in Patients With Type 2 (Non-Insulin-Dependent) Diabetes Mellitus","volume":"35","author":"McVeigh","year":"1992","journal-title":"Diabetologia"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.16.5.705","article-title":"Endothelium-Dependent and -Independent Vasodilation of Large Arteries in Normoalbuminuric Insulin-Dependent Diabetes Mellitus","volume":"16","author":"Lambert","year":"1996","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00540.2002","article-title":"Differential Activation of NF-Kappa B and AP-1 in Increased Fibronectin Synthesis in Target Organs of Diabetic Complications","volume":"284","author":"Chen","year":"2003","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.03-0540","article-title":"Oncofetal Fibronectin in Diabetic Retinopathy","volume":"45","author":"Khan","year":"2004","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.1993.265.5.H1841","article-title":"Paracrine Effects of Endocardial Endothelial Cells on Myocyte Contraction Mediated via Endothelin","volume":"265","author":"Mebazaa","year":"1993","journal-title":"Am J Physiol"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1006\/jmcc.2000.1197","article-title":"Diabetes-Induced Myocardial Structural Changes: Role of Endothelin-1 and its Receptors","volume":"32","author":"Chen","year":"2000","journal-title":"J Mol Cell Cardiol"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2362.2009.02251.x","article-title":"Effects of Transgenic Endothelin-2 Overexpression on Diabetic Cardiomyopathy in Rats","volume":"40","author":"Liefeldt","year":"2010","journal-title":"Eur J Clin Invest"},{"key":"B68","article-title":"Lack of Endothelium-Derived Hyperpolarizing Factor (EDHF) Up-Regulation in Endothelial Dysfunction in Aorta in Diabetic Rats","volume":"59","author":"Csanyi","year":"2007","journal-title":"Pharmacol Rep"},{"key":"B69","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1186\/1475-2840-8-56","article-title":"Nitric Oxide and Superoxide Dismutase Modulate Endothelial Progenitor Cell Function in Type 2 Diabetes Mellitus","volume":"8","author":"Hamed","year":"2009","journal-title":"Cardiovasc Diabetol"},{"key":"B70","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1016\/S0925-4439(00)00078-8","article-title":"Influence of Diabetes on Cardiac Nitric Oxide Synthase Expression and Activity","volume":"1535","author":"Stockklauser-F\u00e4rber","year":"2000","journal-title":"Biochim Biophys Acta"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.02-1284","article-title":"Inner Blood-Retinal Barrier GLUT1 in Long-Term Diabetic Rats: An Immunogold Electron Microscopic Study","volume":"44","author":"Fernandes","year":"2003","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1055\/s-2007-978814","article-title":"Diabetes Mellitus Induces Long Lasting Changes in the Glucose Transporter of Rat Heart Endothelial Cells","volume":"31","author":"Hirsch","year":"1999","journal-title":"Horm Metab Res"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-005-1681-y","article-title":"Delayed Autoregulation of Glucose Transport in Vascular Endothelial Cells","volume":"48","author":"Alpert","year":"2005","journal-title":"Diabetologia"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.2337\/db13-0417","article-title":"A Critical Role for Thioredoxin-Interacting Protein in Diabetes-Related Impairment of Angiogenesis","volume":"63","author":"Dunn","year":"2014","journal-title":"Diabetes"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.111.226340","article-title":"Thioredoxin-Interacting Protein Mediates TRX1 Translocation to the Plasma Membrane in Response to Tumor Necrosis Factor-\u03b1: A Key Mechanism for Vascular Endothelial Growth Factor Receptor-2 Transactivation by Reactive Oxygen Species","volume":"31","author":"World","year":"2011","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.06.037","article-title":"Role of PFKFB3-Driven Glycolysis in Vessel Sprouting","volume":"154","author":"De Bock","year":"2013","journal-title":"Cell"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.201404156","article-title":"Principles of Targeting Endothelial Cell Metabolism to Treat Angiogenesis and Endothelial Cell Dysfunction in Disease","volume":"6","author":"Goveia","year":"2014","journal-title":"EMBO Mol Med"},{"key":"B78","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M007505200","article-title":"High Glucose Inhibits Glucose-6-Phosphate Dehydrogenase via cAMP in Aortic Endothelial Cells","volume":"275","author":"Zhang","year":"2000","journal-title":"J Biol Chem"},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.1096\/fj.00-0893fje","article-title":"Glucose-6-Phosphate Dehydrogenase Deficiency Promotes Endothelial Oxidant Stress and Decreases Endothelial Nitric Oxide Bioavailability","volume":"15","author":"Leopold","year":"2001","journal-title":"FASEB J Off Publ Fed Am Soc Exp Biol"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.1172\/JCI118397","article-title":"Receptor-Mediated Endothelial Cell Dysfunction in Diabetic Vasculopathy. Soluble Receptor for Advanced Glycation End Products Blocks Hyperpermeability in Diabetic Rats","volume":"97","author":"Wautier","year":"1996","journal-title":". J Clin Invest"},{"key":"B81","doi-asserted-by":"publisher","DOI":"10.1097\/HJH.0b013e328335043e","article-title":"Advanced Glycation End-Products Induce Vascular Dysfunction via Resistance to Nitric Oxide and Suppression of Endothelial Nitric Oxide\u00a0Synthase","volume":"28","author":"Soro-Paavonen","year":"2010","journal-title":"J Hypertens"},{"key":"B82","doi-asserted-by":"publisher","DOI":"10.1046\/j.1523-1755.2001.0590051842.x","article-title":"Long-Term Exposure to High Glucose Up-Regulates VCAM-Induced Endothelial Cell Adhesiveness to PBMC","volume":"59","author":"Esposito","year":"2001","journal-title":"Kidney Int"},{"key":"B83","doi-asserted-by":"publisher","first-page":"27","DOI":"10.5551\/jat.RV17014","article-title":"Mechanism of Development of Atherosclerosis and Cardiovascular Disease in Diabetes Mellitus","volume":"25","author":"Katakami","year":"2018","journal-title":"J Atheroscler Thromb"},{"key":"B84","doi-asserted-by":"publisher","DOI":"10.1172\/JCI11235","article-title":"Hyperglycemia Inhibits Endothelial Nitric Oxide Synthase Activity by Posttranslational Modification at the Akt Site","volume":"108","author":"Du","year":"2001","journal-title":"J Clin Invest"},{"key":"B85","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.46.9.1481","article-title":"Advanced Glycation End Product-Induced Activation of NF-kappaB is Suppressed by Alpha-Lipoic Acid in Cultured Endothelial Cells","volume":"46","author":"Bierhaus","year":"1997","journal-title":"Diabetes"},{"key":"B86","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.26.16498","article-title":"Characterization and Functional Analysis of the Promoter of RAGE, the Receptor for Advanced Glycation End Products","volume":"272","author":"Li","year":"1997","journal-title":"J Biol Chem"},{"key":"B87","doi-asserted-by":"publisher","first-page":"1718","DOI":"10.1093\/eurheartj\/ehv134","article-title":"Clinical Diabetic Cardiomyopathy: A Two-Faced Disease With Restrictive and Dilated Phenotypes","volume":"36","author":"Seferovi\u0107","year":"2015","journal-title":"Eur Heart J"},{"key":"B88","doi-asserted-by":"publisher","DOI":"10.2337\/db09-1694","article-title":"Inhibition of Monocyte Adhesion to Endothelial Cells and Attenuation of Atherosclerotic Lesion by a Glucagon-Like Peptide-1 Receptor Agonist, Exendin-4","volume":"59","author":"Arakawa","year":"2010","journal-title":"Diabetes"},{"key":"B89","doi-asserted-by":"publisher","DOI":"10.2337\/db13-1440","article-title":"Identification and Characterization of GLP-1 Receptor-Expressing Cells Using a New Transgenic Mouse Model","volume":"63","author":"Richards","year":"2014","journal-title":"Diabetes"},{"key":"B90","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2797-4","article-title":"Cells of the Adult Human Heart","volume":"588","author":"Litvi\u0148ukov\u00e1","year":"2020","journal-title":"Nature"},{"key":"B91","doi-asserted-by":"publisher","DOI":"10.1113\/JP276758","article-title":"Endothelial Cell-Cardiomyocyte Crosstalk in Heart Development and Disease","volume":"598","author":"Colliva","year":"2020","journal-title":"J Physiol"},{"key":"B92","doi-asserted-by":"publisher","DOI":"10.3389\/fcvm.2021.790612","article-title":"IL-6\/STAT3 Signaling Promotes Cardiac Dysfunction by Upregulating FUNDC1-Dependent Mitochondria-Associated Endoplasmic Reticulum Membranes Formation in Sepsis Mice","volume":"8","author":"Jiang","year":"2021","journal-title":"Front Cardiovasc Med"},{"key":"B93","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.15147","article-title":"Inhibition of Interleukin-6\/Glycoprotein 130 Signalling by Bazedoxifene Ameliorates Cardiac Remodelling in Pressure Overload Mice","volume":"24","author":"Shi","year":"2020","journal-title":"J Cell Mol Med"},{"key":"B94","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaa0079","article-title":"METABOLISM. S-Nitrosylation Links Obesity-Associated Inflammation to Endoplasmic Reticulum Dysfunction","volume":"349","author":"Yang","year":"2015","journal-title":"Sci (New York NY)"},{"key":"B95","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1038\/s41586-018-0749-z","article-title":"Metabolic Reprogramming by the S-Nitroso-CoA Reductase System Protects Against Kidney Injury","volume":"565","author":"Zhou","year":"2019","journal-title":"Nature"},{"key":"B96","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.105.581397","article-title":"Glycated Proteins Stimulate Reactive Oxygen Species Production in Cardiac Myocytes: Involvement of Nox2 (Gp91phox)-Containing NADPH Oxidase","volume":"113","author":"Zhang","year":"2006","journal-title":"Circulation"},{"key":"B97","doi-asserted-by":"publisher","DOI":"10.1111\/j.1582-4934.2008.00547.x","article-title":"Advanced Glycation Endproduct (AGE) Accumulation and AGE Receptor (RAGE) Up-Regulation Contribute to the Onset of Diabetic Cardiomyopathy","volume":"13","author":"Ma","year":"2009","journal-title":"J Cell Mol Med"},{"key":"B98","doi-asserted-by":"publisher","DOI":"10.1007\/s001250051676","article-title":"15th Golgi Lecture: From Hyperglycaemia to the Dysregulation of Vascular Remodelling in Diabetes","volume":"44","author":"Di Mario","year":"2001","journal-title":"Diabetologia"},{"key":"B99","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2005.01.135","article-title":"Glucose-Induced Serum- and Glucocorticoid-Regulated Kinase Activation in Oncofetal Fibronectin Expression","volume":"329","author":"Khan","year":"2005","journal-title":"Biochem Biophys Res Commun"},{"key":"B100","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-003-1156-y","article-title":"Alteration in Haemodynamics and Pathological Changes in the Cardiovascular System During the Development of Type 2 Diabetes Mellitus in OLETF Rats","volume":"46","author":"Saito","year":"2003","journal-title":"Diabetologia"},{"key":"B101","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2014.00123","article-title":"Fibroblasts in Fibrosis: Novel Roles and Mediators","volume":"5","author":"Kendall","year":"2014","journal-title":"Front Pharmacol"},{"key":"B102","doi-asserted-by":"publisher","first-page":"S5","DOI":"10.1186\/1755-1536-5-S1-S5","article-title":"The Myofibroblast, Multiple Origins for Major Roles in Normal and Pathological Tissue Repair","volume":"5","author":"Micallef","year":"2012","journal-title":"Fibrogenesis Tissue Repair"},{"key":"B103","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexmp.2017.03.007","article-title":"High Glucose Induced Endothelial to Mesenchymal Transition in Human Umbilical Vein Endothelial Cell","volume":"102","author":"Yu","year":"2017","journal-title":"Exp Mol Pathol"},{"key":"B104","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1007\/s10456-018-9639-0","article-title":"The Therapeutic Potential of Targeting the Endothelial-to-Mesenchymal Transition","volume":"22","author":"Man","year":"2019","journal-title":"Angiogenesis"},{"key":"B105","doi-asserted-by":"publisher","first-page":"14361","DOI":"10.1038\/ncomms14361","article-title":"The Molecular Basis of Endothelial Cell Plasticity","volume":"8","author":"Dejana","year":"2017","journal-title":"Nat Commun"},{"key":"B106","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00021.2018","article-title":"Endothelial to Mesenchymal Transition: Role in Physiology and in the Pathogenesis of Human Diseases","volume":"99","author":"Piera-Velazquez","year":"2019","journal-title":"Physiol Rev"},{"key":"B107","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.683594","article-title":"EndMT Regulation by Small RNAs in Diabetes-Associated Fibrotic Conditions: Potential Link With Oxidative Stress","volume":"9","author":"Giordo","year":"2021","journal-title":"Front Cell Dev Biol"},{"key":"B108","doi-asserted-by":"publisher","first-page":"5211","DOI":"10.1038\/s41467-020-18957-w","article-title":"Stress-Induced RNA-Chromatin Interactions Promote Endothelial Dysfunction","volume":"11","author":"Calandrelli","year":"2020","journal-title":"Nat Commun"},{"key":"B109","doi-asserted-by":"publisher","DOI":"10.1161\/hc0302.102143","article-title":"Decreased Cardiac Expression of Vascular Endothelial Growth Factor and its Receptors in Insulin-Resistant and Diabetic States: A Possible Explanation for Impaired Collateral Formation in Cardiac Tissue","volume":"105","author":"Chou","year":"2002","journal-title":"Circulation"},{"key":"B110","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1161\/hy1201.097292","article-title":"Gene Transfer of cGMP-Dependent Protein Kinase I Enhances the Antihypertrophic Effects of Nitric Oxide in Cardiomyocytes","volume":"39","author":"Wollert","year":"2002","journal-title":"Hypertens (Dallas Tex 1979)"},{"key":"B111","doi-asserted-by":"publisher","first-page":"165833","DOI":"10.1016\/j.bbadis.2020.165833","article-title":"Targeting Endothelial Exosomes for the Prevention of Cardiovascular Disease","volume":"1866","author":"Jia","year":"2020","journal-title":"Biochim Biophys Acta Mol Basis Dis"},{"key":"B112","doi-asserted-by":"publisher","DOI":"10.1016\/S0033-0620(96)80005-3","article-title":"The Cardiac Endothelium: Cardioactive Mediators","volume":"39","author":"Shah","year":"1996","journal-title":"Prog Cardiovasc Dis"},{"key":"B113","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1093\/cvr\/cvab013","article-title":"Endothelial Cell Metabolic Memory Causes Cardiovascular Dysfunction In Diabetes","volume":"118","author":"Yao","year":"2021","journal-title":"Cardiovasc Res"},{"key":"B114","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.23.22.8226-8232.2003","article-title":"Cardiomyocyte-Specific Endothelin A Receptor Knockout Mice Have Normal Cardiac Function and an Unaltered Hypertrophic Response to Angiotensin II and Isoproterenol","volume":"23","author":"Kedzierski","year":"2003","journal-title":"Mol Cell Biol"},{"key":"B115","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardiores.2004.04.015","article-title":"Heme Oxygenase-1 Inhibition of MAP Kinases, Calcineurin\/NFAT Signaling, and Hypertrophy in Cardiac Myocytes","volume":"63","author":"Tongers","year":"2004","journal-title":"Cardiovasc Res"},{"key":"B116","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.01003.2004","article-title":"Prostacyclin Attenuates Oxidative Damage of Myocytes by Opening Mitochondrial ATP-Sensitive K+ Channels via the EP3 Receptor","volume":"288","author":"Shinmura","year":"2005","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"B117","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2009.04.060","article-title":"Neuregulin1\/ErbB4 Signaling Induces Cardiomyocyte Proliferation and Repair of Heart Injury","volume":"138","author":"Bersell","year":"2009","journal-title":"Cell"},{"key":"B118","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2006.08.013","article-title":"Opposing Cardiovascular Roles for the Angiotensin and Apelin Signaling Pathways","volume":"41","author":"Ashley","year":"2006","journal-title":"J Mol Cell Cardiol"},{"key":"B119","doi-asserted-by":"publisher","DOI":"10.1007\/s12265-014-9582-4","article-title":"Imaging Subclinical Atherosclerosis: Is it Ready for Prime Time? A Review","volume":"7","author":"Fern\u00e1ndez-Friera","year":"2014","journal-title":"J Cardiovasc Transl Res"},{"key":"B120","doi-asserted-by":"publisher","DOI":"10.1111\/bph.13517","article-title":"Targeting Vascular (Endothelial) Dysfunction","volume":"174","author":"Daiber","year":"2017","journal-title":"Br J Pharmacol"},{"key":"B121","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1007\/s10741-013-9388-5","article-title":"Structural Changes in the Myocardium During Diabetes-Induced Cardiomyopathy","volume":"19","author":"Adeghate","year":"2014","journal-title":"Heart Fail Rev"},{"key":"B122","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbalip.2011.10.001","article-title":"Lipoprotein Lipase Mediated Fatty Acid Delivery and Its Impact in Diabetic Cardiomyopathy","volume":"1821","author":"Kim","year":"2012","journal-title":"Biochim Biophys Acta"},{"key":"B123","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.01.015","article-title":"Single-Cell Transcriptome Atlas of Murine Endothelial Cells","volume":"180","author":"Kalucka","year":"2020","journal-title":"Cell"},{"key":"B124","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1007\/s00395-020-0798-y","article-title":"Microvascular and Lymphatic Dysfunction in HFpEF and Its Associated Comorbidities","volume":"115","author":"Cuijpers","year":"2020","journal-title":"Basic Res Cardiol"},{"key":"B125","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.120.314370","article-title":"Lymphatic and Immune Cell Cross-Talk Regulates Cardiac Recovery After Experimental Myocardial Infarction","volume":"40","author":"Houssari","year":"2020","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"B126","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2020.10.022","article-title":"Reduced Lymphatic Reserve in Heart Failure With Preserved Ejection Fraction","volume":"76","author":"Rossitto","year":"2020","journal-title":"J Am Coll Cardiol"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2022.851941\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,7]],"date-time":"2022-04-07T04:41:00Z","timestamp":1649306460000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2022.851941\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,7]]},"references-count":126,"alternative-id":["10.3389\/fendo.2022.851941"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2022.851941","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,7]]},"article-number":"851941"}}