{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T16:22:28Z","timestamp":1789662148778,"version":"4.0.1"},"reference-count":81,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2024,12,21]],"date-time":"2024-12-21T00:00:00Z","timestamp":1734739200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002428","name":"Austrian Science Fund FWF","doi-asserted-by":"publisher","award":["PAT8808224"],"award-info":[{"award-number":["PAT8808224"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Medical University of Graz","award":["PAT8808224"],"award-info":[{"award-number":["PAT8808224"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Endothelial dysfunction is a hallmark of several pathological conditions, including cancer, cardiovascular disease and inflammatory disorders. In these conditions, perturbed TCA cycle and subsequent succinate accumulation have been reported. The role of succinate as a regulator of immunological responses and inflammation is increasingly being recognized. Nevertheless, how endothelial cell function and phenotype are altered by elevated intracellular succinate has not been addressed yet. Thus, we employed numerous in vitro functional assays using primary HUVECs and diethyl succinate (DES), a cell membrane-permeable succinate analogue. An MTS assay 1 h post stimulation with DES suggested reduced metabolic activity in HUVECs. Concurrently, elevated production of ROS, including mitochondrial superoxide, and a reduction in mitochondrial membrane potential were observed. These findings were corroborated by Seahorse mito-stress testing, which revealed that DES acutely lowered the OCR, maximal respiration and ATP production. Given the link between mitochondrial stress and apoptosis, we examined important survival signalling pathways. DES transiently reduced ERK1\/2 phosphorylation, a response that was followed by a skewed pro-apoptotic shift in the BAX to BCL2L1 gene expression ratio, which coincided with upregulating VEGF gene expression. This indicated an induction of mixed pro-apoptotic and pro-survival signals in the cell. However, the BAX\/BCL-XL protein ratio was unchanged, suggesting that the cells did not commit themselves to apoptosis. An MTS assay, caspase 3\/7 activity assay and annexin V\/propidium iodide staining confirmed this finding. By contrast, stimulation with DES induced acute endothelial barrier permeability, forming intercellular gaps, altering cell size and associated actin filaments without affecting cell count. Notably, during overnight DES exposure gradual recovery of the endothelial barrier and cell sprouting was observed, alongside mitochondrial membrane potential restoration, albeit with sustained ROS production. COX-2 inhibition and EP4 receptor blockade hindered barrier restoration, implicating a role of COX-2\/PGE2\/EP4 signalling in this process. Interestingly, ascorbic acid pre-treatment prevented DES-induced acute barrier disruption independently from ROS modulation. In conclusion, succinate acts as a significant regulator of endothelial mitochondrial function and barrier integrity, a response that is counterbalanced by upregulated VEGF and prostaglandin production by the endothelial cells.<\/jats:p>","DOI":"10.3390\/antiox13121579","type":"journal-article","created":{"date-parts":[[2024,12,23]],"date-time":"2024-12-23T04:33:29Z","timestamp":1734928409000},"page":"1579","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Succinate Regulates Endothelial Mitochondrial Function and Barrier Integrity"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7184-4882","authenticated-orcid":false,"given":"Reham","family":"Atallah","sequence":"first","affiliation":[{"name":"Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, 8010 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6155-5208","authenticated-orcid":false,"given":"Juergen","family":"Gindlhuber","sequence":"additional","affiliation":[{"name":"Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Physiology & Pathophysiology, Medical University of Graz, 8010 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfgang","family":"Platzer","sequence":"additional","affiliation":[{"name":"Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, 8010 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0279-6431","authenticated-orcid":false,"given":"Rishi","family":"Rajesh","sequence":"additional","affiliation":[{"name":"Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, 8010 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8554-2372","authenticated-orcid":false,"given":"Akos","family":"Heinemann","sequence":"additional","affiliation":[{"name":"Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, 8010 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.1161\/CIRCULATIONAHA.106.652859","article-title":"Endothelial Function and Dysfunction","volume":"115","author":"Deanfield","year":"2007","journal-title":"Circulation"},{"key":"ref_2","first-page":"1","article-title":"The Endothelium, Part I: Multiple Functions of the Endothelial Cells\u2014Focus on Endothelium-Derived Vasoactive Mediators","volume":"3","year":"2011","journal-title":"Colloq. Ser. Integr. Syst. Physiol. Mol. Funct."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Amedei, A., and Morbidelli, L. (2019). Circulating Metabolites Originating from Gut Microbiota Control Endothelial Cell Function. Molecules, 24.","DOI":"10.3390\/molecules24213992"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"8965","DOI":"10.1126\/sciadv.abm8965","article-title":"Lactate Induces Vascular Permeability via Disruption of VE-Cadherin in Endothelial Cells during Sepsis","volume":"8","author":"Yang","year":"2022","journal-title":"Sci. Adv."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/j.atherosclerosis.2016.08.011","article-title":"Endothelial Cell Metabolism: A Novel Player in Atherosclerosis? Basic Principles and Therapeutic Opportunities","volume":"253","author":"Pircher","year":"2016","journal-title":"Atherosclerosis"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1038\/s41556-021-00637-6","article-title":"Control of Endothelial Quiescence by FOXO-Regulated Metabolites","volume":"23","author":"Andrade","year":"2021","journal-title":"Nat. Cell Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1016\/j.cell.2013.06.037","article-title":"Role of PFKFB3-Driven Glycolysis in Vessel Sprouting","volume":"154","author":"Georgiadou","year":"2013","journal-title":"Cell"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"4845","DOI":"10.3390\/cimb46050292","article-title":"Contribution of Endothelial Dysfunction to Cancer Susceptibility and Progression: A Comprehensive Narrative Review on the Genetic Risk Component","volume":"46","author":"Tavares","year":"2024","journal-title":"Curr. Issues Mol. Biol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Sun, H.J., Wu, Z.Y., Nie, X.W., and Bian, J.S. (2019). Role of Endothelial Dysfunction in Cardiovascular Diseases: The Link Between Inflammation and Hydrogen Sulfide. Front. Pharmacol., 10.","DOI":"10.3389\/fphar.2019.01568"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"81","DOI":"10.14336\/AD.2015.0803","article-title":"Chronic Inflammatory Diseases and Endothelial Dysfunction","volume":"7","author":"Castellon","year":"2016","journal-title":"Aging Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1038\/s41467-019-13668-3","article-title":"Mitochondrial TCA Cycle Metabolites Control Physiology and Disease","volume":"11","author":"Chandel","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Choi, I., Son, H., and Baek, J.H. (2021). Tricarboxylic Acid (TCA) Cycle Intermediates: Regulators of Immune Responses. Life, 11.","DOI":"10.3390\/life11010069"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1038\/s42255-024-00981-5","article-title":"Monocarboxylate Transporters Facilitate Succinate Uptake into Brown Adipocytes","volume":"6","author":"Reddy","year":"2024","journal-title":"Nat. Metab."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"111193","DOI":"10.1016\/j.celrep.2022.111193","article-title":"Succinate Uptake by T Cells Suppresses Their Effector Function via Inhibition of Mitochondrial Glucose Oxidation","volume":"40","author":"Gudgeon","year":"2022","journal-title":"Cell Rep."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1042\/BJ20081386","article-title":"How Mitochondria Produce Reactive Oxygen Species","volume":"417","author":"Murphy","year":"2009","journal-title":"Biochem. J."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1038\/s41568-020-00303-3","article-title":"2-Oxoglutarate-Dependent Dioxygenases in Cancer","volume":"20","author":"Losman","year":"2020","journal-title":"Nat. Rev. Cancer"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.freeradbiomed.2018.07.009","article-title":"Succinate Induces Synovial Angiogenesis in Rheumatoid Arthritis through Metabolic Remodeling and HIF-1\u03b1\/VEGF Axis","volume":"126","author":"Li","year":"2018","journal-title":"Free Radic. Biol. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1038\/nature11986","article-title":"Succinate Is an Inflammatory Signal That Induces IL-1\u03b2 through HIF-1\u03b1","volume":"496","author":"Tannahill","year":"2013","journal-title":"Nature"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Weber, A., Klocker, H., Oberacher, H., Gnaiger, E., Neuwirt, H., Sampson, N., and Eder, I.E. (2018). Succinate Accumulation Is Associated with a Shift of Mitochondrial Respiratory Control and HIF-1\u03b1 Upregulation in PTEN Negative Prostate Cancer Cells. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19072129"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1038\/nature02488","article-title":"Citric Acid Cycle Intermediates as Ligands for Orphan G-Protein-Coupled Receptors","volume":"429","author":"He","year":"2004","journal-title":"Nature"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Wang, L., Zhang, Y., Kiprowska, M., Guo, Y., Yamamoto, K., and Li, X. (2021). Diethyl Succinate Modulates Microglial Polarization and Activation by Reducing Mitochondrial Fission and Cellular ROS. Metabolites, 11.","DOI":"10.3390\/metabo11120854"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.1084\/jem.20160061","article-title":"GPR91 Senses Extracellular Succinate Released from Inflammatory Macrophages and Exacerbates Rheumatoid Arthritis","volume":"213","author":"Sarret","year":"2016","journal-title":"J. Exp. Med."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Atallah, R., Gindlhuber, J., Platzer, W., B\u00e4rnthaler, T., Tatzl, E., Toller, W., Strutz, J., Rittchen, S., Luschnig, P., and Birner-gruenberger, R. (2021). SUCNR1 Is Expressed in Human Placenta and Mediates Angiogenesis: Significance in Gestational Diabetes. Int. J. Mol. Sci., 22.","DOI":"10.20944\/preprints202110.0291.v1"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/nmeth.2019","article-title":"Fiji: An Open-Source Platform for Biological-Image Analysis","volume":"9","author":"Schindelin","year":"2012","journal-title":"Nat. Methods"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1182\/blood.2022016090","article-title":"Acquired Mutations in BAX Confer Resistance to BH3-Mimetic Therapy in Acute Myeloid Leukemia","volume":"141","author":"Moujalled","year":"2023","journal-title":"Blood"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.ejphar.2004.08.003","article-title":"Cyclooxygenase Inhibition in Human Monocytes Increases Endotoxin-Induced TNF\u03b1 without Affecting Cyclooxygenase-2 Expression","volume":"501","author":"Ulcar","year":"2004","journal-title":"Eur. J. Pharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Matlac, D.M., Hadrava Vanova, K., Bechmann, N., Richter, S., Folberth, J., Ghayee, H.K., Ge, G.B., Abunimer, L., Wesley, R., and Aherrahrou, R. (2021). Succinate Mediates Tumorigenic Effects via Succinate Receptor 1: Potential for New Targeted Treatment Strategies in Succinate Dehydrogenase Deficient Paragangliomas. Front. Endocrinol., 12.","DOI":"10.3389\/fendo.2021.589451"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"13174","DOI":"10.18632\/oncotarget.14485","article-title":"Oncometabolite Succinate Promotes Angiogenesis by Upregulating VEGF Expression through GPR91-Mediated STAT3 and ERK Activation","volume":"8","author":"Mu","year":"2017","journal-title":"Oncotarget"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1186\/s12933-021-01333-3","article-title":"Elevated Plasma Succinate Levels Are Linked to Higher Cardiovascular Disease Risk Factors in Young Adults","volume":"20","author":"Di","year":"2021","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1021\/ja2040865","article-title":"Real Time Molecular Imaging of TCA Cycle Metabolism in Vivo By Hyperpolarized 1-13C Diethyl Succinate","volume":"134","author":"Zacharias","year":"2012","journal-title":"J. Am. Chem. Soc."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.ccr.2004.11.022","article-title":"Succinate Links TCA Cycle Dysfunction to Oncogenesis by Inhibiting HIF-\u03b1 Prolyl Hydroxylase","volume":"7","author":"Selak","year":"2005","journal-title":"Cancer Cell"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1016\/j.cell.2016.08.064","article-title":"Succinate Dehydrogenase Supports Metabolic Repurposing of Mitochondria to Drive Inflammatory Macrophages","volume":"167","author":"Mills","year":"2016","journal-title":"Cell"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1159\/000257490","article-title":"Changes in Human Endothelial Cell Energy Metabolic Capacities during in Vitro Cultivation. The Role of \u201cAerobic Glycolysis\u201d and Proliferation","volume":"24","author":"Peters","year":"2009","journal-title":"Cell Physiol. Biochem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"600","DOI":"10.3109\/10799893.2015.1030412","article-title":"Signaling Pathway of MAPK\/ERK in Cell Proliferation, Differentiation, Migration, Senescence and Apoptosis","volume":"35","author":"Sun","year":"2015","journal-title":"J. Recept. Signal Transduct."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1171","DOI":"10.1042\/bst0311171","article-title":"VEGF Signalling: Integration and Multi-Tasking in Endothelial Cell Biology","volume":"31","author":"Zachary","year":"2003","journal-title":"Biochem. Soc. Trans."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1039\/c3ib40223a","article-title":"Global Architecture of the F-Actin Cytoskeleton Regulates Cell Shape-Dependent Endothelial Mechanotransduction","volume":"6","author":"Shao","year":"2014","journal-title":"Integr. Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1113\/jphysiol.2004.076075","article-title":"The Protein Kinase MEK1\/2 Mediate Vascular Endothelial Growth Factor- and Histamine-Induced Hyperpermeability in Porcine Coronary Venules","volume":"563","author":"Wu","year":"2004","journal-title":"J. Physiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2831","DOI":"10.4049\/jimmunol.167.5.2831","article-title":"Roles of Cyclooxygenase (COX)-1 and COX-2 in Prostanoid Production by Human Endothelial Cells: Selective up-Regulation of Prostacyclin Synthesis by COX-2","volume":"167","author":"Caughey","year":"2001","journal-title":"J. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2504","DOI":"10.1016\/j.yexcr.2007.03.036","article-title":"Prostaglandins PGE2 and PGI2 Promote Endothelial Barrier Enhancement via PKA- and Epac1\/Rap1-Dependent Rac Activation","volume":"313","author":"Birukova","year":"2007","journal-title":"Exp. Cell Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1002\/mc.20736","article-title":"Diclofenac, a Selective COX-2 Inhibitor, Inhibits DMH-Induced Colon Tumorigenesis through Suppression of MCP-1, MIP-1\u03b1 and VEGF","volume":"50","author":"Kaur","year":"2011","journal-title":"Mol. Carcinog."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"45838","DOI":"10.1074\/jbc.M209213200","article-title":"Prostaglandin E2 Promotes Integrin AV\u03b23-Dependent Endothelial Cell Adhesion, Rac-Activation, and Spreading through CAMP\/PKA-Dependent Signaling","volume":"277","author":"Dormond","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1038\/emm.2005.72","article-title":"Prostaglandin E2 Stimulates Angiogenesis by Activating the Nitric Oxide\/CGMP Pathway in Human Umbilical Vein Endothelial Cells","volume":"37","author":"Namkoong","year":"2005","journal-title":"Exp. Mol. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/bs.vh.2022.10.008","article-title":"Ascorbic Acid as Antioxidant","volume":"121","author":"Skrzydlewska","year":"2023","journal-title":"Vitam. Horm."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1038\/nature13909","article-title":"Ischaemic Accumulation of Succinate Controls Reperfusion Injury through Mitochondrial ROS","volume":"515","author":"Chouchani","year":"2014","journal-title":"Nature"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1016\/j.jhep.2007.03.016","article-title":"Succinate Is a Paracrine Signal for Liver Damage","volume":"47","author":"Correa","year":"2007","journal-title":"J. Hepatol."},{"key":"ref_46","first-page":"1172","article-title":"Which Concentrations Are Optimal for in Vitro Testing?","volume":"19","author":"Albrecht","year":"2020","journal-title":"EXCLI J."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1038\/nrm3722","article-title":"Control of Apoptosis by the BCL-2 Protein Family: Implications for Physiology and Therapy","volume":"15","author":"Czabotar","year":"2013","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"178","DOI":"10.3322\/canjclin.55.3.178","article-title":"Targeting Apoptosis Pathways in Cancer Therapy","volume":"55","author":"Ghobrial","year":"2005","journal-title":"CA Cancer J. Clin."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1080\/01926230701320337","article-title":"Apoptosis: A Review of Programmed Cell Death","volume":"35","author":"Elmore","year":"2007","journal-title":"Toxicol. Pathol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1038\/s41418-023-01153-w","article-title":"Apoptotic Cell Death in Disease\u2014Current Understanding of the NCCD 2023","volume":"30","author":"Vitale","year":"2023","journal-title":"Cell Death Differ."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Swiderska, A., Coney, A.M., Alzahrani, A.A., Aldossary, H.S., Batis, N., Ray, C.J., Kumar, P., and Holmes, A.P. (2021). Mitochondrial Succinate Metabolism and Reactive Oxygen Species Are Important but Not Essential for Eliciting Carotid Body and Ventilatory Responses to Hypoxia in the Rat. Antioxidants, 10.","DOI":"10.3390\/antiox10060840"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1453","DOI":"10.1111\/j.1538-7836.2008.03087.x","article-title":"Endothelial Cell Junctions and the Regulation of Vascular Permeability and Leukocyte Transmigration","volume":"6","author":"Aghajanian","year":"2008","journal-title":"J. Thromb. Haemost."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"6600","DOI":"10.1126\/sciadv.adf6600","article-title":"Succinate Metabolism and Membrane Reorganization Drives the Endotheliopathy and Coagulopathy of Traumatic Hemorrhage","volume":"9","author":"Abdullah","year":"2023","journal-title":"Sci. Adv."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"25602","DOI":"10.1074\/jbc.M109.009894","article-title":"The Regulation of Vascular Endothelial Growth Factor-Induced Microvascular Permeability Requires Rac and Reactive Oxygen Species","volume":"284","author":"Burridge","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.1152\/ajpheart.01037.2008","article-title":"Calcium Influx-Dependent Differential Actions of Superoxide and Hydrogen Peroxide on Microvessel Permeability","volume":"296","author":"Zhou","year":"2009","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1007\/s00424-017-1935-9","article-title":"Hypoxia and Aerobic Metabolism Adaptations of Human Endothelial Cells","volume":"469","author":"Koziel","year":"2017","journal-title":"Pflug. Arch."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1874","DOI":"10.1084\/jem.20182151","article-title":"Endothelial ERK1\/2 Signaling Maintains Integrity of the Quiescent Endothelium","volume":"216","author":"Ricard","year":"2019","journal-title":"J. Exp. Med."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"L360","DOI":"10.1152\/ajplung.2000.279.2.L360","article-title":"Role of Ras-Dependent ERK Activation in Phorbol Ester-Induced Endothelial Cell Barrier Dysfunction","volume":"279","author":"Verin","year":"2000","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1097\/00024382-200207000-00015","article-title":"The Role of P38 Map Kinase in Tumor Necrosis Factor-Induced Redistribution of Vascular Endothelial Cadherin and Increased Endothelial Permeability","volume":"18","author":"Nwariaku","year":"2002","journal-title":"Shock"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1038\/s41419-018-0708-5","article-title":"Succinate Induces Aberrant Mitochondrial Fission in Cardiomyocytes through GPR91 Signaling","volume":"9","author":"Lu","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"C467","DOI":"10.1152\/ajpcell.00327.2022","article-title":"Succinate-SUCNR1 Induces Renal Tubular Cell Apoptosis","volume":"324","author":"Pu","year":"2023","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1038\/s42255-021-00389-5","article-title":"UCP1 Governs Liver Extracellular Succinate and Inflammatory Pathogenesis","volume":"3","author":"Mills","year":"2021","journal-title":"Nat. Metab."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"H485","DOI":"10.1152\/ajpheart.00035.2016","article-title":"Fluid Shear Stress Induces Upregulation of COX-2 and PGI2 Release in Endothelial Cells via a Pathway Involving PECAM-1, PI3K, FAK, and P38","volume":"312","author":"Adams","year":"2017","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1074\/jbc.272.1.601","article-title":"Hypoxia Induces Cyclooxygenase-2 via the NF-\u039aB P65 Transcription Factor in Human Vascular Endothelial Cells","volume":"272","author":"Schmedtje","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"9049","DOI":"10.1016\/S0021-9258(18)52976-8","article-title":"Molecular Cloning of Human Prostaglandin Endoperoxide Synthase Type II and Demonstration of Expression in Response to Cytokines","volume":"268","author":"Jones","year":"1993","journal-title":"J. Biol. Chem."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"3847","DOI":"10.1002\/jcp.24097","article-title":"Cytoskeletal Architecture Regulates Cyclooxygenase-2 in Human Endothelial Cells: Autocrine Modulation by Prostacyclin","volume":"227","author":"Eligini","year":"2012","journal-title":"J. Cell. Physiol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1161\/01.CIR.0000051367.92927.07","article-title":"High Glucose Causes Upregulation of Cyclooxygenase-2 and Alters Prostanoid Profile in Human Endothelial Cells","volume":"107","author":"Cosentino","year":"2003","journal-title":"Circulation"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"5423","DOI":"10.4049\/jimmunol.175.8.5423","article-title":"Oxidative Stress Augments the Production of Matrix Metalloproteinase-1, Cyclooxygenase-2, and Prostaglandin E2 through Enhancement of NF-\u039aB Activity in Lipopolysaccharide-Activated Human Primary Monocytes","volume":"175","author":"Lu","year":"2005","journal-title":"J. Immunol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"30","DOI":"10.21037\/jtd.2017.01.23","article-title":"The Role of Cyclooxygenase-2 in the Protection against Apoptosis in Vascular Endothelial Cells Induced by Cigarette Smoking","volume":"9","author":"Shi","year":"2017","journal-title":"J. Thorac. Dis."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"C1038","DOI":"10.1152\/ajpcell.2001.281.3.C1038","article-title":"Regulation of PGE2 and PGI2 Release from Human Umbilical Vein Endothelial Cells by Actin Cytoskeleton","volume":"281","author":"Sawyer","year":"2001","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Rittchen, S., Rohrer, K., Platzer, W., Knuplez, E., B\u00e4rnthaler, T., Marsh, L.M., Atallah, R., Sinn, K., Klepetko, W., and Sharma, N. (2020). Prostaglandin D2 Strengthens Human Endothelial Barrier by Activation of E-Type Receptor 4. Biochem. Pharmacol., 182.","DOI":"10.1016\/j.bcp.2020.114277"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1016\/j.jaci.2012.05.008","article-title":"Endothelial E-Type Prostanoid 4 Receptors Promote Barrier Function and Inhibit Neutrophil Trafficking","volume":"131","author":"Konya","year":"2013","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"4524","DOI":"10.1074\/jbc.M610415200","article-title":"Inhibition of Hypoxia-Inducible Factor (HIF) Hydroxylases by Citric Acid Cycle Intermediates Possible Links Between Cell Metabolism and Stabilization of hif","volume":"282","author":"Koivunen","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"2515","DOI":"10.1021\/acs.chemrestox.0c00348","article-title":"Nuclear and Cytoplasmic Functions of Vitamin C","volume":"33","author":"Zhitkovich","year":"2020","journal-title":"Chem. Res. Toxicol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1152\/ajplung.00300.2011","article-title":"Mechanisms of Attenuation of Abdominal Sepsis Induced Acute Lung Injury by Ascorbic Acid","volume":"303","author":"Fisher","year":"2012","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1002\/jcp.1041630219","article-title":"Ascorbic Acid Stimulates Barrier Function of Cultured Endothelial Cell Monolayer","volume":"163","author":"Utoguchi","year":"1995","journal-title":"J. Cell Physiol."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Ulker, E., Parker, W.H., Raj, A., Qu, Z., and May, J.M. (2016). Ascorbic Acid Prevents VEGF-Induced Increases in Endothelial Barrier Permeability. Mol. Cell Biochem., 412.","DOI":"10.1007\/s11010-015-2609-6"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1016\/j.bbrc.2017.11.058","article-title":"Ascorbic Acid Attenuates Endothelial Permeability Triggered by Cell-Free Hemoglobin","volume":"495","author":"Kuck","year":"2018","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1359","DOI":"10.3109\/10715762.2010.508496","article-title":"Ascorbic Acid Prevents Increased Endothelial Permeability Caused by Oxidized Low Density Lipoprotein","volume":"44","author":"May","year":"2010","journal-title":"Free Radic. Res."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"21486","DOI":"10.1074\/jbc.M115.662098","article-title":"Intracellular Sscorbate Prevents Endothelial Barrier Permeabilization by Thrombin","volume":"290","author":"Parker","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1111\/odi.12446","article-title":"Vitamin C Physiology: The Known and the Unknown And","volume":"22","author":"Padayatty","year":"2016","journal-title":"Oral Dis."}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/13\/12\/1579\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:57:39Z","timestamp":1760115459000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/13\/12\/1579"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,21]]},"references-count":81,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["antiox13121579"],"URL":"https:\/\/doi.org\/10.3390\/antiox13121579","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,21]]}}}