Endothelial dysfunction: molecular mechanisms and clinical implications

Abstract

Cardiovascular disease (CVD) and its complications are a leading cause of death worldwide. Endothelial dysfunction plays a crucial role in the initiation and progression of CVD, serving as a pivotal factor in the pathogenesis of cardiovascular, metabolic, and other related diseases. The regulation of endothelial dysfunction is influenced by various risk factors and intricate signaling pathways, which vary depending on the specific disease context. Despite numerous research efforts aimed at elucidating the mechanisms underlying endothelial dysfunction, the precise molecular pathways involved remain incompletely understood. This review elucidates recent research findings on the pathophysiological mechanisms involved in endothelial dysfunction, including nitric oxide availability, oxidative stress, and inflammation-mediated pathways. We also discuss the impact of endothelial dysfunction on various pathological conditions, including atherosclerosis, heart failure, diabetes, hypertension, chronic kidney disease, and neurodegenerative diseases. Furthermore, we summarize the traditional and novel potential biomarkers of endothelial dysfunction as well as pharmacological and nonpharmacological therapeutic strategies for endothelial protection and treatment for CVD and related complications. Consequently, this review is to improve understanding of emerging biomarkers and therapeutic approaches aimed at reducing the risk of developing CVD and associated complications, as well as mitigating endothelial dysfunction.

Keywords

cardiovascular disease / endothelial dysfunction / inflammation / nitric oxide / oxidative stress

References

[1] Poredos P, Poredos AV, Gregoric I. Endothelial dysfunction and its clinical implications. Angiology. 2021; 72(7): 604-615.

[2] Leite AR, Borges-Canha M, Cardoso R, et al. Novel biomarkers for evaluation of endothelial dysfunction. Angiology. 2020; 71(5): 397-410.

[3] Shi Y, Vanhoutte PM. Macro-and microvascular endothelial dysfunction in diabetes. J Diabetes. 2017; 9(5): 434-449.

[4] Waclawovsky AJ, de Brito E, Smith L, et al. Endothelial dysfunction in people with depressive disorders: a systematic review and meta-analysis. J Psychiatr Res. 2021; 141: 152-159.

[5] Sara J, Prasad M, Zhang M, et al. High-sensitivity C-reactive protein is an independent marker of abnormal coronary vasoreactivity in patients with non-obstructive coronary artery disease. Am Heart J. 2017; 190: 1-11.

[6] Ridker PM, MacFadyen JG, Glynn RJ, et al. Comparison of interleukin-6, C-reactive protein, and low-density lipoprotein cholesterol as biomarkers of residual risk in contemporary practice: secondary analyses from the cardiovascular inflammation reduction trial. Eur Heart J. 2020; 41(31): 2952-2961.

[7] Jang S, Palzer EF, Rudser KD, et al. Relationship of endothelial microparticles to obesity and cardiovascular disease risk in children and adolescents. J Am Heart Assoc. 2022; 11(22): e026430.

[8] Oduro PK, Fang J, Niu L, et al. Pharmacological management of vascular endothelial dysfunction in diabetes: TCM and western medicine compared based on biomarkers and biochemical parameters. Pharmacol Res. 2020; 158: 104893.

[9] Bai S, Yin Q, Dong T, et al. Endothelial progenitor cell-derived exosomes ameliorate endothelial dysfunction in a mouse model of diabetes. Biomed Pharmacother. 2020; 131: 110756.

[10] Medina-Leyte DJ, Zepeda-Garcia O, Dominguez-Perez M, et al. Endothelial dysfunction, inflammation and coronary artery disease: potential biomarkers and promising therapeutical approaches. Int J Mol Sci. 2021; 22(8).

[11] Feenstra L, Kutikhin AG, Shishkova DK, et al. Calciprotein particles induce endothelial dysfunction by impairing endothelial nitric oxide metabolism. ArteriosclerThrombVasc Biol. 2023; 43(3): 443-455.

[12] Shaito A, Aramouni K, Assaf R, et al. Oxidative stress-induced endothelial dysfunction in cardiovascular diseases. Front Biosci (Landmark Ed). 2022; 27(3): 105.

[13] Chen X, Li W, Chang C. NR3C2 mediates oxidised low-density lipoprotein-induced human coronary endothelial cells dysfunction via modulation of NLRP3 inflammasome activation. Autoimmunity. 2023; 56(1): 2189135.

[14] Li T, Qiu J, Jia T, et al. G3BP2 regulates oscillatory shear stress-induced endothelial dysfunction. Genes Dis. 2022; 9(6): 1701-1715.

[15] Jiang T, Jiang D, Zhang L, Ding M, Zhou H. Anagliptin ameliorates high glucose-induced endothelial dysfunction via suppression of NLRP3 inflammasome activation mediated by SIRT1. Mol Immunol. 2019; 107: 54-60.

[16] Karbach S, Wenzel P, Waisman A, Munzel T, Daiber A. eNOS uncoupling in cardiovascular diseases–the role of oxidative stress and inflammation. Curr Pharm Des. 2014; 20(22): 3579-3594.

[17] Poznyak AV, Grechko AV, Orekhova VA, et al. Oxidative stress and antioxidants in atherosclerosis development and treatment. Biology (Basel). 2020; 9(3).

[18] Wang X, Fu W, Zhou G, et al. Endothelial cell-derived cholesterol crystals promote endothelial inflammation in early atherogenesis. Antioxid Redox Signal. 2024;.

[19] Cyr AR, Huckaby LV, Shiva SS, Zuckerbraun BS. Nitric oxide and endothelial dysfunction. Crit Care Clin. 2020; 36(2): 307-321.

[20] Heiss EH, Dirsch VM. Regulation of eNOS enzyme activity by posttranslational modification. Curr Pharm Des. 2014; 20(22): 3503-3513.

[21] Sharma NM, Patel KP. Post-translational regulation of neuronal nitric oxide synthase: implications for sympathoexcitatory states. Expert Opin Ther Targets. 2017; 21(1): 11-22.

[22] Hess DT, Stamler JS. Regulation by S-nitrosylation of protein post-translational modification. J Biol Chem. 2012; 287(7): 4411-4418.

[23] Forstermann U, Sessa WC. Nitric oxide synthases: regulation and function. Eur Heart J. 2012; 33(7): 829-837, 837a-837d.

[24] Fleming I, Busse R. Molecular mechanisms involved in the regulation of the endothelial nitric oxide synthase. Am J Physiol Regul Integr Comp Physiol. 2003; 284(1): R1-12.

[25] Siragusa M, Oliveira JA, Malacarne PF, et al. VE-PTP inhibition elicits eNOS phosphorylation to blunt endothelial dysfunction and hypertension in diabetes. Cardiovasc Res. 2021; 117(6): 1546-1556.

[26] Li L, Wang X, Zheng L, et al. Downregulation of endothelin A receptor (ETaR) ameliorates renal ischemia reperfusion injury by increasing nitric oxide production. Life Sci. 2019; 228: 295-304.

[27] Liao FF, Lin G, Chen X, et al. Endothelial nitric oxide synthase-deficient mice: a model of spontaneous cerebral small-vessel disease. Am J Pathol. 2021; 191(11): 1932-1945.

[28] Musicante M, Kim HH, Chen Y, et al. Regulation of endothelial nitric oxide synthase in cardiac remodeling. Int J Cardiol. 2022; 364: 96-101.

[29] Lu L, Jang S, Zhu J, et al. Nur77 mitigates endothelial dysfunction through activation of both nitric oxide production and anti-oxidant pathways. Redox Biol. 2024; 70: 103056.

[30] Fernandes D, Khambata RS, Massimo G, et al. Local delivery of nitric oxide prevents endothelial dysfunction in periodontitis. Pharmacol Res. 2023; 188: 106616.

[31] Maloney SE, Broberg CA, Grayton QE, et al. Role of nitric oxide-releasing glycosaminoglycans in wound healing. Acs Biomater Sci Eng. 2022; 8(6): 2537-2552.

[32] Lundberg JO, Gladwin MT, Weitzberg E. Strategies to increase nitric oxide signalling in cardiovascular disease. Nat Rev Drug Discov. 2015; 14(9): 623-641.

[33] Farah C, Michel L, Balligand JL. Nitric oxide signalling in cardiovascular health and disease. Nat Rev Cardiol. 2018; 15(5): 292-316.

[34] De Maria R, Campolo J, Frontali M, et al. Effects of sapropterin on endothelium-dependent vasodilation in patients with CADASIL: a randomized controlled trial. Stroke. 2014; 45(10): 2959-2966.

[35] Gori T, Burstein JM, Ahmed S, et al. Folic acid prevents nitroglycerin-induced nitric oxide synthase dysfunction and nitrate tolerance: a human in vivo study. Circulation. 2001; 104(10): 1119-1123.

[36] Daiber A, Munzel T. Organic nitrate therapy, nitrate tolerance, and nitrate-induced endothelial dysfunction: emphasis on redox biology and oxidative stress. Antioxid Redox Signal. 2015; 23(11): 899-942.

[37] Gradinaru D, Borsa C, Ionescu C, Prada GI. Oxidized LDL and NO synthesis–biomarkers of endothelial dysfunction and ageing. Mech Ageing Dev. 2015; 151: 101-113.

[38] Xu S, Xu Y, Liu P, et al. The novel coronary artery disease risk gene JCAD/KIAA1462 promotes endothelial dysfunction and atherosclerosis. Eur Heart J. 2019; 40(29): 2398-2408.

[39] Haas MJ, Feng V, Gonzales K, Onstead-Haas L, Mooradian AD. High-throughput analysis identifying drugs that reduce oxidative and ER stress in human coronary artery endothelial cells. Eur J Pharmacol. 2020; 879: 173119.

[40] Ko J, Kang HJ, Kim DA, et al. Uric acid induced the phenotype transition of vascular endothelial cells via induction of oxidative stress and glycocalyx shedding. Faseb J. 2019; 33(12): 13334-13345.

[41] Sun L, Liu YL, Ye F, et al. Free fatty acid-induced H(2)O(2) activates TRPM2 to aggravate endothelial insulin resistance via Ca(2+)-dependent PERK/ATF4/TRB3 cascade in obese mice. Free Radic Biol Med. 2019; 143: 288-299.

[42] Rao K, Shen X, Pardue S, Krzywanski DM. Nicotinamide nucleotide transhydrogenase (NNT) regulates mitochondrial ROS and endothelial dysfunction in response to angiotensin II. Redox Biol. 2020; 36: 101650.

[43] Schulz E, Wenzel P, Munzel T, Daiber A. Mitochondrial redox signaling: Interaction of mitochondrial reactive oxygen species with other sources of oxidative stress. Antioxid Redox Signal. 2014; 20(2): 308-324.

[44] Liu Z, Liu Y, Xu Q, et al. Critical role of vascular peroxidase 1 in regulating endothelial nitric oxide synthase. Redox Biol. 2017; 12: 226-232.

[45] Lovatt M, Adnan K, Kocaba V, et al. Peroxiredoxin-1 regulates lipid peroxidation in corneal endothelial cells. Redox Biol. 2020; 30: 101417.

[46] Birk M, Baum E, Zadeh JK, et al. Angiotensin II induces oxidative stress and endothelial dysfunction in mouse ophthalmic arteries via involvement of AT1 receptors and NOX2. Antioxidants (Basel). 2021; 10(8).

[47] Nasoni MG, Crinelli R, Iuliano L, Luchetti F. When nitrosative stress hits the endoplasmic reticulum: possible implications in oxLDL/oxysterols-induced endothelial dysfunction. Free Radic Biol Med. 2023; 208: 178-185.

[48] Dikalova AE, Pandey A, Xiao L, et al. Mitochondrial deacetylase Sirt3 reduces vascular dysfunction and hypertension while sirt3 depletion in essential hypertension is linked to vascular inflammation and oxidative stress. Circ Res. 2020; 126(4): 439-452.

[49] Scioli MG, Storti G, D’Amico F, et al. Oxidative stress and new pathogenetic mechanisms in endothelial dysfunction: potential diagnostic biomarkers and therapeutic targets. J Clin Med. 2020; 9(6).

[50] Khaw KT, Bingham S, Welch A, et al. Relation between plasma ascorbic acid and mortality in men and women in EPIC-Norfolk prospective study: a prospective population study. European Prospective Investigation into Cancer and Nutrition. Lancet. 2001; 357(9257): 657-663.

[51] Ziegler D, Nowak H, Kempler P, Vargha P, Low PA. Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a meta-analysis. Diabet Med. 2004; 21(2): 114-121.

[52] Shuaib A, Lees KR, Lyden P, et al. NXY-059 for the treatment of acute ischemic stroke. N Engl J Med. 2007; 357(6): 562-571.

[53] Bredemeier M, Lopes LM, Eisenreich MA, et al. Xanthine oxidase inhibitors for prevention of cardiovascular events: a systematic review and meta-analysis of randomized controlled trials. BMC Cardiovasc Disord. 2018; 18(1): 24.

[54] Zhou Y, Tai S, Zhang N, Fu L, Wang Y. Dapagliflozin prevents oxidative stress-induced endothelial dysfunction via sirtuin 1 activation. Biomed Pharmacother. 2023; 165: 115213.

[55] Yu J, Wang S, Shi W, et al. Roxadustat prevents Ang II hypertension by targeting angiotensin receptors and eNOS. JCI Insight. 2021; 6(18).

[56] Xiao X, Xu M, Yu H, et al. Correction to: mesenchymal stem cell-derived small extracellular vesicles mitigate oxidative stress-induced senescence in endothelial cells via regulation of miR-146a/Src. Signal Transduct Target Ther. 2022; 7(1): 234.

[57] Pan Q, Wang Y, Liu J, et al. MiR-17-5p mediates the effects of ACE2-enriched endothelial progenitor cell-derived exosomes on ameliorating cerebral ischemic injury in aged mice. Mol Neurobiol. 2023; 60(6): 3534-3552.

[58] Montiel V, Lobysheva I, Gerard L, et al. Oxidative stress-induced endothelial dysfunction and decreased vascular nitric oxide in COVID-19 patients. Ebiomedicine. 2022; 77: 103893.

[59] Nannapaneni SS, Nimmanapalli HD, Lakshmi AY, Vishnubotla SK. Markers of oxidative stress, inflammation, and endothelial dysfunction in diabetic and nondiabetic patients with chronic kidney disease on peritoneal dialysis. Saudi J Kidney Dis Transpl. 2022; 33(3): 361-372.

[60] Bassu S, Zinellu A, Sotgia S, et al. Oxidative stress biomarkers and peripheral endothelial dysfunction in rheumatoid arthritis: a monocentric cross-sectional case-control study. Molecules. 2020; 25(17).

[61] Premer C, Kanelidis AJ, Hare JM, Schulman IH. Rethinking endothelial dysfunction as a crucial target in fighting heart failure. Mayo Clin Proc Innov Qual Outcomes. 2019; 3(1): 1-13.

[62] Li X, Fang P, Sun Y, et al. Anti-inflammatory cytokines IL-35 and IL-10 block atherogenic lysophosphatidylcholine-induced, mitochondrial ROS-mediated innate immune activation, but spare innate immune memory signature in endothelial cells. Redox Biol. 2020; 28: 101373.

[63] Yau JW, Teoh H, Verma S. Endothelial cell control of thrombosis. BMC Cardiovasc Disord. 2015; 15: 130.

[64] Doring Y, Soehnlein O, Weber C. Neutrophil extracellular traps in atherosclerosis and atherothrombosis. Circ Res. 2017; 120(4): 736-743.

[65] Schafer MJ, Zhang X, Kumar A, et al. The senescence-associated secretome as an indicator of age and medical risk. JCI Insight. 2020; 5(12).

[66] Krouwer VJ, Hekking LH, Langelaar-Makkinje M, Regan-Klapisz E, Post JA. Endothelial cell senescence is associated with disrupted cell-cell junctions and increased monolayer permeability. Vasc Cell. 2012; 4(1): 12.

[67] Yanaka M, Honma T, Sato K, et al. Increased monocytic adhesion by senescence in human umbilical vein endothelial cells. Biosci Biotechnol Biochem. 2011; 75(6): 1098-1103.

[68] Hwang HJ, Lee YR, Kang D, et al. Endothelial cells under therapy-induced senescence secrete CXCL11, which increases aggressiveness of breast cancer cells. Cancer Lett. 2020; 490: 100-110.

[69] Khan SY, Awad EM, Oszwald A, et al. Premature senescence of endothelial cells upon chronic exposure to TNFalpha can be prevented by N-acetyl cysteine and plumericin. Sci Rep. 2017; 7: 39501.

[70] Bidault G, Garcia M, Capeau J, et al. Progerin expression induces inflammation, oxidative stress and senescence in human coronary endothelial cells. Cells-Basel. 2020; 9(5).

[71] Shosha E, Xu Z, Narayanan SP, et al. Mechanisms of diabetes-induced endothelial cell senescence: role of arginase 1. Int J Mol Sci. 2018; 19(4).

[72] Jiang YH, Jiang LY, Wang YC, Ma DF, Li X. Quercetin attenuates atherosclerosis via modulating oxidized LDL-induced endothelial cellular senescence. Front Pharmacol. 2020; 11: 512.

[73] Zhang M, Lin JM, Li XS, Li J. Quercetin ameliorates LPS-induced inflammation in human peripheral blood mononuclear cells by inhibition of the TLR2-NF-kappaB pathway. Genet Mol Res. 2016; 15(2).

[74] Chandel S, Sathis A, Dhar M, et al. Hyperinsulinemia promotes endothelial inflammation via increased expression and release of Angiopoietin-2. Atherosclerosis. 2020; 307: 1-10.

[75] Zeng Y, Xu J, Hua YQ, Peng Y, Xu XL. MDM2 contributes to oxidized low-density lipoprotein-induced inflammation through modulation of mitochondrial damage in endothelial cells. Atherosclerosis. 2020; 305: 1-9.

[76] Wang KC, Yeh YT, Nguyen P, et al. Flow-dependent YAP/TAZ activities regulate endothelial phenotypes and atherosclerosis. P Natl Acad Sci USA. 2016; 113(41): 11525-11530.

[77] Xu S, Koroleva M, Yin M, Jin ZG. Atheroprotective laminar flow inhibits Hippo pathway effector YAP in endothelial cells. Transl Res. 2016; 176: 18-28.e2.

[78] Zhou Y, Little PJ, Downey L, et al. The role of Toll-like receptors in atherothrombotic cardiovascular disease. ACS Pharmacol Transl Sci. 2020; 3(3): 457-471.

[79] Song W, Zhang CL, Gou L, et al. Endothelial TFEB (transcription factor EB) restrains IKK (IkappaB Kinase)-p65 pathway to attenuate vascular inflammation in diabetic db/db mice. Arterioscler Thromb Vasc Biol. 2019; 39(4): 719-730.

[80] SenBanerjee S, Lin Z, Atkins GB, et al. KLF2 Is a novel transcriptional regulator of endothelial proinflammatory activation. J Exp Med. 2004; 199(10): 1305-1315.

[81] Hamik A, Lin Z, Kumar A, et al. Kruppel-like factor 4 regulates endothelial inflammation. J Biol Chem. 2007; 282(18): 13769-13779.

[82] Roche-Molina M, Hardwick B, Sanchez-Ramos C, et al. The pharmaceutical solvent N-methyl-2-pyrollidone (NMP) attenuates inflammation throughKruppel-like factor 2 activation to reduce atherogenesis. Sci Rep. 2020; 10(1): 11636.

[83] Marti CN, Gheorghiade M, Kalogeropoulos AP, et al. Endothelial dysfunction, arterial stiffness, and heart failure. J Am Coll Cardiol. 2012; 60(16): 1455-1469.

[84] Al HH, Jomaa S, Jabra M, Alhouri AN, Latifeh Y. Pathophysiology of stress cardiomyopathy: a comprehensive literature review. Ann Med Surg (Lond). 2022; 82: 104671.

[85] Giannitsi S, Bougiakli M, Bechlioulis A, Naka K. Endothelial dysfunction and heart failure: a review of the existing bibliography with emphasis on flow mediated dilation. JRSM Cardiovasc Dis. 2019; 8: 2048004019843047.

[86] Chignalia AZ, Isbatan A, Patel M, et al. Pressure-dependent NOS activation contributes to endothelial hyperpermeability in a model of acute heart failure. Biosci Rep. 2018; 38(6).

[87] Alem MM. Endothelial dysfunction in chronic heart failure: assessment, findings, significance, and potential therapeutic targets. Int J Mol Sci. 2019; 20(13).

[88] Vancheri F, Longo G, Vancheri S, Henein M. Coronary microvascular dysfunction. J Clin Med. 2020; 9(9).

[89] Zuchi C, Tritto I, Carluccio E, et al. Role of endothelial dysfunction in heart failure. Heart Fail Rev. 2020; 25(1): 21-30.

[90] Wang M, Li Y, Li S, Lv J. Endothelial dysfunction and diabetic cardiomyopathy. Front Endocrinol (Lausanne). 2022; 13: 851941.

[91] Veitch S, Njock MS, Chandy M, et al. MiR-30 promotes fatty acid beta-oxidation and endothelial cell dysfunction and is a circulating biomarker of coronary microvascular dysfunction in pre-clinical models of diabetes. Cardiovasc Diabetol. 2022; 21(1): 31.

[92] Dai M, Wang Y, Peng L, et al. Relationship between quantitative parameters of echocardiography and vascular endothelial function in patients with chronic heart failure and its predictive value for short-term MACE risk. J Healthc Eng. 2021; 2021: 1985962.

[93] Hulshoff MS, Xu X, Krenning G, Zeisberg EM. Epigenetic regulation of endothelial-to-mesenchymal transition in chronic heart disease. ArteriosclerThrombVasc Biol. 2018; 38(9): 1986-1996.

[94] Ji L, Su S, Xin M, et al. Luteolin ameliorates hypoxia-induced pulmonary hypertension via regulating HIF-2alpha-Arg-NO axis and PI3K-AKT-eNOS-NO signaling pathway. Phytomedicine. 2022; 104: 154329.

[95] Piatek K, Feuerstein A, Zach V, et al. Nitric oxide metabolites: associations with cardiovascular biomarkers and clinical parameters in patients with HFpEF. ESC Heart Fail. 2022; 9(6): 3961-3972.

[96] Touyz RM, Montezano AC, Rios F, Widlansky ME, Liang M. Redox stress defines the small artery vasculopathy of hypertension: how do we bridge the bench-to-bedside gap? Circ Res. 2017; 120(11): 1721-1723.

[97] Davies MJ, Gordon JL, Gearing AJ, et al. The expression of the adhesion molecules ICAM-1, VCAM-1, PECAM, and E-selectin in human atherosclerosis. J Pathol. 1993; 171(3): 223-229.

[98] Gordon E, Schimmel L, Frye M. The importance of mechanical forces for in vitro endothelial cell biology. Front Physiol. 2020; 11: 684.

[99] Roger VL, Weston SA, Killian JM, et al. Time trends in the prevalence of atherosclerosis: a population-based autopsy study. Am J Med. 2001; 110(4): 267-273.

[100] Targonski P, Jacobsen SJ, Weston SA, et al. Referral to autopsy: effect of antemortem cardiovascular disease: a population-based study in Olmsted County, Minnesota. Ann Epidemiol. 2001; 11(4): 264-270.

[101] Canham L, Sendac S, Diagbouga MR, et al. EVA1A (Eva-1 homolog A) promotes endothelial apoptosis and inflammatory activation under disturbed flow via regulation of autophagy. ArteriosclerThrombVasc Biol. 2023; 43(4): 547-561.

[102] Mazzi V, De Nisco G, Hoogendoorn A, et al. Early atherosclerotic changes in coronary arteries are associated with endothelium shear stress contraction/expansion variability. Ann Biomed Eng. 2021; 49(9): 2606-2621.

[103] Katakia YT, Kanduri S, Bhattacharyya R, et al. Angular difference in human coronary artery governs endothelial cell structure and function. Commun Biol. 2022; 5(1): 1044.

[104] Minamino T, Miyauchi H, Yoshida T, et al. Endothelial cell senescence in human atherosclerosis: role of telomere in endothelial dysfunction. Circulation. 2002; 105(13): 1541-1544.

[105] van der Feen DE, Bossers G, Hagdorn Q, et al. Cellular senescence impairs the reversibility of pulmonary arterial hypertension. Sci Transl Med. 2020; 12(554).

[106] Gimbrone MJ, Garcia-Cardena G. Endothelial cell dysfunction and the pathobiology of atherosclerosis. Circ Res. 2016; 118(4): 620-636.

[107] Silva GC, Abbas M, Khemais-Benkhiat S, et al. Replicative senescence promotes prothrombotic responses in endothelial cells: Role of NADPH oxidase-and cyclooxygenase-derived oxidative stress. Exp Gerontol. 2017; 93: 7-15.

[108] Bochenek ML, Schutz E, Schafer K. Endothelial cell senescence and thrombosis: ageing clots. Thromb Res. 2016; 147: 36-45.

[109] Zhu HY, Hong FF, Yang SL. The roles of nitric oxide synthase/nitric oxide pathway in the pathology of vascular dementia and related therapeutic approaches. Int J Mol Sci. 2021; 22(9).

[110] Batko K, Krzanowski M, Pietrzycka A, et al. Interplay of nitric oxide metabolites and markers of endothelial injury, inflammation, and vascular disease in the spectrum of advanced chronic kidney disease. Kardiol Pol. 2020; 78(1): 51-58.

[111] Tsihlis ND, Oustwani CS, Vavra AK, et al. Nitric oxide inhibits vascular smooth muscle cell proliferation and neointimal hyperplasia by increasing the ubiquitination and degradation of UbcH10. Cell BiochemBiophys. 2011; 60(1-2): 89-97.

[112] Cui Z, Zhao X, Amevor FK, et al. Therapeutic application of quercetin in aging-related diseases: SIRT1 as a potential mechanism. Front Immunol. 2022; 13: 943321.

[113] Guo Z, Li P, Ge J, Li H. SIRT6 in aging, metabolism, inflammation and cardiovascular diseases. Aging Dis. 2022; 13(6): 1787-1822.

[114] Abraham CR, Li A. Aging-suppressor Klotho: Prospects in diagnostics and therapeutics. Ageing Res Rev. 2022; 82: 101766.

[115] Minami S, Sakai S, Yamamoto T, et al. FGF21 and autophagy coordinately counteract kidney disease progression during aging and obesity. Autophagy. 2024; 20(3): 489-504.

[116] Hecker A, Schellnegger M, Hofmann E, et al. The impact of resveratrol on skin wound healing, scarring, and aging. Int Wound J. 2022; 19(1): 9-28.

[117] An JY, Kerns KA, Ouellette A, et al. Rapamycin rejuvenates oral health in aging mice. eLife. 2020; 9.

[118] Wei R, Su Z, Mackenzie GG. Chlorogenic acid combined with epigallocatechin-3-gallate mitigates D-galactose-induced gut aging in mice. Food Funct. 2023; 14(6): 2684-2697.

[119] Alexander Y, Osto E, Schmidt-Trucksass A, et al. Endothelial function in cardiovascular medicine: a consensus paper of the European Society of Cardiology Working Groups on Atherosclerosis and Vascular Biology, Aorta and Peripheral Vascular Diseases, Coronary Pathophysiology and Microcirculation, and Thrombosis. Cardiovasc Res. 2021; 117(1): 29-42.

[120] Zhao Y, Vanhoutte PM, Leung SW. Vascular nitric oxide: beyond eNOS. J Pharmacol Sci. 2015; 129(2): 83-94.

[121] Schiffrin EL. How structure, mechanics, and function of the vasculature contribute to blood pressure elevation in hypertension. Can J Cardiol. 2020; 36(5): 648-658.

[122] Siti HN, Kamisah Y, Kamsiah J. The role of oxidative stress, antioxidants and vascular inflammation in cardiovascular disease (a review). VasculPharmacol. 2015; 71: 40-56.

[123] Shimokawa H, Godo S. Nitric oxide and endothelium-dependent hyperpolarization mediated by hydrogen peroxide in health and disease. Basic Clin PharmacolToxicol. 2020; 127(2): 92-101.

[124] Souilhol C, Serbanovic-Canic J, Fragiadaki M, et al. Endothelial responses to shear stress in atherosclerosis: a novel role for developmental genes. Nat Rev Cardiol. 2020; 17(1): 52-63.

[125] Vinaiphat A, Pazhanchamy K, JebaMercy G, et al. Endothelial damage arising from high salt hypertension is elucidated by vascular bed systematic profiling. ArteriosclerThrombVasc Biol. 2023; 43(3): 427-442.

[126] Kusche-Vihrog K, Schmitz B, Brand E. Salt controls endothelial and vascular phenotype. Pflugers Arch. 2015; 467(3): 499-512.

[127] Chien S, Shyy JY. Effects of hemodynamic forces on gene expression and signal transduction in endothelial cells. Biol Bull. 1998; 194(3): 390-391; discussion 392–3.

[128] Shah MS, Brownlee M. Molecular and cellular mechanisms of cardiovascular disorders in diabetes. Circ Res. 2016; 118(11): 1808-1829.

[129] Baig N, Sultan R, Qureshi SA. Antioxidant and anti-inflammatory activities of Centratherumanthelminticum (L.) Kuntze seed oil in diabetic nephropathy via modulation of Nrf-2/HO-1 and NF-kappaB pathway. BMC Complement Med Ther. 2022; 22(1): 301.

[130] Nishikawa T, Edelstein D, Du XL, et al. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature. 2000; 404(6779): 787-790.

[131] Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature. 2001; 414(6865): 813-820.

[132] Yamagishi SI, Matsui T. Role of hyperglycemia-induced advanced glycation end product (AGE) accumulation in atherosclerosis. Ann Vasc Dis. 2018; 11(3): 253-258.

[133] Ruiz HH, Ramasamy R, Schmidt AM. Advanced glycation end products: building on the concept of the “common soil” in metabolic disease. Endocrinology. 2020; 161(1).

[134] Wautier JL, Schmidt AM. Protein glycation: a firm link to endothelial cell dysfunction. Circ Res. 2004; 95(3): 233-238.

[135] Banarjee R, Sharma A, Bai S, Deshmukh A, Kulkarni M. Proteomic study of endothelial dysfunction induced by AGEs and its possible role in diabetic cardiovascular complications. J Proteomics. 2018; 187: 69-79.

[136] Adamopoulos C, Piperi C, Gargalionis AN, et al. Advanced glycation end products upregulate lysyl oxidase and endothelin-1 in human aortic endothelial cells via parallel activation of ERK1/2-NF-kappaB and JNK-AP-1 signaling pathways. Cell Mol Life Sci. 2016; 73(8): 1685-1698.

[137] Ren X, Ren L, Wei Q, et al. Advanced glycation end-products decreases expression of endothelial nitric oxide synthase through oxidative stress in human coronary artery endothelial cells. Cardiovasc Diabetol. 2017; 16(1): 52.

[138] Jing C, Zhang G, Liu Z, et al. Peroxidasin promotes diabetic vascular endothelial dysfunction induced by advanced glycation end products via NOX2/HOCl/Akt/eNOS pathway. Redox Biol. 2021; 45: 102031.

[139] Chen YH, Chen ZW, Li HM, Yan XF, Feng B. AGE/RAGE-Induced EMP Release via the NOX-Derived ROS Pathway. J Diabetes Res. 2018; 2018: 6823058.

[140] Querfeld U, Mak RH, Pries AR. Microvascular disease in chronic kidney disease: the base of the iceberg in cardiovascular comorbidity. Clin Sci (Lond). 2020; 134(12): 1333-1356.

[141] Jain V, Gupta K, Bhatia K, et al. Coronary flow abnormalities in chronic kidney disease: a systematic review and meta-analysis. Echocardiography. 2022; 39(11): 1382-1390.

[142] Schoina M, Loutradis C, Memmos E, et al. Microcirculatory function deteriorates with advancing stages of chronic kidney disease independently of arterial stiffness and atherosclerosis. Hypertens Res. 2021; 44(2): 179-187.

[143] Zoccali C. Endothelial dysfunction and the kidney: emerging risk factors for renal insufficiency and cardiovascular outcomes in essential hypertension. J Am Soc Nephrol. 2006; 17(4 Suppl 2): S61-63.

[144] Fliser D, Wiecek A, Suleymanlar G, et al. The dysfunctional endothelium in CKD and in cardiovascular disease: mapping the origin(s) of cardiovascular problems in CKD and of kidney disease in cardiovascular conditions for a research agenda. Kidney Int Suppl (2011). 2011; 1(1): 6-9.

[145] Peyster E, Chen J, Feldman HI, et al. Inflammation and arterial stiffness in chronic kidney disease: findings from the CRIC study. Am J Hypertens. 2017; 30(4): 400-408.

[146] Gupta J, Dominic EA, Fink JC, et al. Association between inflammation and cardiac geometry in chronic kidney disease: findings from the CRIC study. PLoS One. 2015; 10(4): e0124772.

[147] Amdur RL, Feldman HI, Gupta J, et al. Inflammation and progression of CKD: the CRIC study. Clin J Am Soc Nephrol. 2016; 11(9): 1546-1556.

[148] van der Vorm LN, Visser R, Huskens D, et al. Circulating active von Willebrand factor levels are increased in chronic kidney disease and end-stage renal disease. Clin Kidney J. 2020; 13(1): 72-74.

[149] Wu-Wong JR, Kawai M, Chen YW, et al. Two novel vitamin D receptor modulators with similar structures exhibit different hypercalcemic effects in 5/6 nephrectomized uremic rats. Am J Nephrol. 2013; 37(4): 310-319.

[150] Vila CM, Ferrantelli E, Meinster E, et al. Vitamin D attenuates endothelial dysfunction in uremic rats and maintains human endothelial stability. J Am Heart Assoc. 2018; 7(17): e008776.

[151] Padberg JS, Wiesinger A, di Marco GS, et al. Damage of the endothelial glycocalyx in chronic kidney disease. Atherosclerosis. 2014; 234(2): 335-343.

[152] Six I, Gross P, Remond MC, et al. Deleterious vascular effects of indoxyl sulfate and reversal by oral adsorbent AST-120. Atherosclerosis. 2015; 243(1): 248-256.

[153] Verkaik M, Juni RP, van Loon E, et al. FGF23 impairs peripheral microvascular function in renal failure. Am J Physiol Heart Circ Physiol. 2018; 315(5): H1414-H1424.

[154] Ermert K, Buhl EM, Klinkhammer BM, Floege J, Boor P. Reduction of endothelial glycocalyx on peritubular capillaries in chronic kidney disease. Am J Pathol. 2023; 193(2): 138-147.

[155] Ehling J, Babickova J, Gremse F, et al. Quantitative micro-computed tomography imaging of vascular dysfunction in progressive kidney diseases. J Am Soc Nephrol. 2016; 27(2): 520-532.

[156] Charytan DM, Skali H, Shah NR, et al. Coronary flow reserve is predictive of the risk of cardiovascular death regardless of chronic kidney disease stage. Kidney Int. 2018; 93(2): 501-509.

[157] Mihai S, Codrici E, Popescu ID, et al. Inflammation-related mechanisms in chronic kidney disease prediction, progression, and outcome. J Immunol Res. 2018; 2018: 2180373.

[158] Stenvinkel P, Ketteler M, Johnson RJ, et al. IL-10, IL-6, and TNF-alpha: central factors in the altered cytokine network of uremia–the good, the bad, and the ugly. Kidney Int. 2005; 67(4): 1216-1233.

[159] Gupta J, Mitra N, Kanetsky PA, et al. Association between albuminuria, kidney function, and inflammatory biomarker profile in CKD in CRIC. Clin J Am Soc Nephrol. 2012; 7(12): 1938-1946.

[160] Wang CC, Lee AS, Liu SH, et al. Spironolactone ameliorates endothelial dysfunction through inhibition of the AGE/RAGE axis in a chronic renal failure rat model. Bmc Nephrol. 2019; 20(1): 351.

[161] Speer T, Owala FO, Holy EW, et al. Carbamylated low-density lipoprotein induces endothelial dysfunction. Eur Heart J. 2014; 35(43): 3021-3032.

[162] Perez L, Vallejos A, Echeverria C, et al. OxHDL controls LOX-1 expression and plasma membrane localization through a mechanism dependent on NOX/ROS/NF-kappaB pathway on endothelial cells. Lab Invest. 2019; 99(3): 421-437.

[163] Speer T, Rohrer L, Blyszczuk P, et al. Abnormal high-density lipoprotein induces endothelial dysfunction via activation of Toll-like receptor-2. Immunity. 2013; 38(4): 754-768.

[164] Fels B, Beyer A, Cazana-Perez V, et al. Effects of chronic kidney disease on nanomechanics of the endothelial glycocalyx are mediated by the mineralocorticoid receptor. Int J Mol Sci. 2022; 23(18).

[165] Harlacher E, Wollenhaupt J, Baaten C, Noels H. Impact of uremic toxins on endothelial dysfunction in chronic kidney disease: a systematic review. Int J Mol Sci. 2022; 23(1).

[166] Stafim DCR, Gregorio PC, Maciel R, et al. Uremic toxins activate CREB/ATF1 in endothelial cells related to chronic kidney disease. BiochemPharmacol. 2022; 198: 114984.

[167] Goldin A, Beckman JA, Schmidt AM, Creager MA. Advanced glycation end products: sparking the development of diabetic vascular injury. Circulation. 2006; 114(6): 597-605.

[168] Vila CM, van Bezu J, Beelen R, Vervloet MG, Hordijk PL. Stabilization of cell-cell junctions by active vitamin D ameliorates uraemia-induced loss of human endothelial barrier function. Nephrol Dial Transplant. 2019; 34(2): 252-264.

[169] Lin CJ, Wu V, Wu PC, Wu CJ. Meta-analysis of the associations of p-cresyl sulfate (PCS) and indoxyl sulfate (IS) with cardiovascular events and all-cause mortality in patients with chronic renal failure. PLoS One. 2015; 10(7): e0132589.

[170] Sweeney MD, Sagare AP, Zlokovic BV. Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat Rev Neurol. 2018; 14(3): 133-150.

[171] Sweeney MD, Zhao Z, Montagne A, Nelson AR, Zlokovic BV. Blood-brain barrier: from physiology to disease and back. Physiol Rev. 2019; 99(1): 21-78.

[172] Yuan Y, Sun J, Dong Q, Cui M. Blood-brain barrier endothelial cells in neurodegenerative diseases: signals from the “barrier”. Front Neurosci. 2023; 17: 1047778.

[173] Carrera-Gonzalez M, Canton-Habas V, Rich-Ruiz M. Aging, depression and dementia: the inflammatory process. Adv Clin Exp Med. 2022; 31(5): 469-473.

[174] Kook SY, Seok HH, Moon M, Mook-Jung I. Disruption of blood-brain barrier in Alzheimer disease pathogenesis. Tissue Barriers. 2013; 1(2): e23993.

[175] Kurz C, Walker L, Rauchmann BS, Perneczky R. Dysfunction of the blood-brain barrier in Alzheimer’s disease: evidence from human studies. Neuropathol Appl Neurobiol. 2022; 48(3): e12782.

[176] Nation DA, Sweeney MD, Montagne A, et al. Blood-brain barrier breakdown is an early biomarker of human cognitive dysfunction. Nat Med. 2019; 25(2): 270-276.

[177] Montagne A, Nation DA, Sagare AP, et al. APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline. Nature. 2020; 581(7806): 71-76.

[178] Carrano A, Hoozemans JJ, van der Vies SM, et al. Neuroinflammation and blood-brain barrier changes in capillary amyloid angiopathy. Neurodegener Dis. 2012; 10(1-4): 329-331.

[179] Shigemoto-Mogami Y, Hoshikawa K, Sato K. Activated microglia disrupt the blood-brain barrier and induce chemokines and cytokines in a rat in vitro model. Front Cell Neurosci. 2018; 12: 494.

[180] Reed MJ, Damodarasamy M, Banks WA. The extracellular matrix of the blood-brain barrier: structural and functional roles in health, aging, and Alzheimer’s disease. Tissue Barriers. 2019; 7(4): 1651157.

[181] Rempe RG, Hartz A, Soldner E, et al. Matrix metalloproteinase-mediated blood-brain barrier dysfunction in epilepsy. J Neurosci. 2018; 38(18): 4301-4315.

[182] Pijet B, Stefaniuk M, Kostrzewska-Ksiezyk A, et al. Elevation of MMP-9 levels promotes epileptogenesis after traumatic brain injury. Mol Neurobiol. 2018; 55(12): 9294-9306.

[183] Diaz-Galvan P, Lorenzon G, Mohanty R, et al. Differential response to donepezil in MRI subtypes of mild cognitive impairment. Alzheimers Res Ther. 2023; 15(1): 117.

[184] Ongnok B, Khuanjing T, Chunchai T, et al. Donepezil protects against doxorubicin-induced chemobrain in rats via attenuation of inflammation and oxidative stress without interfering with doxorubicin efficacy. Neurotherapeutics. 2021; 18(3): 2107-2125.

[185] Broekaart DW, Bertran A, Jia S, et al. The matrix metalloproteinase inhibitor IPR-179 has antiseizure and antiepileptogenic effects. J Clin Invest. 2021; 131(1).

[186] Benincasa G, Coscioni E, Napoli C. Cardiovascular risk factors and molecular routes underlying endothelial dysfunction: Novel opportunities for primary prevention. BiochemPharmacol. 2022; 202: 115108.

[187] Horio E, Kadomatsu T, Miyata K, et al. Role of endothelial cell-derived angptl2 in vascular inflammation leading to endothelial dysfunction and atherosclerosis progression. ArteriosclerThrombVasc Biol. 2014; 34(4): 790-800.

[188] Hata J, Mukai N, Nagata M, et al. Serum angiopoietin-like protein 2 is a novel risk factor for cardiovascular disease in the community: the Hisayama Study. ArteriosclerThrombVascBiol. 2016; 36(8): 1686-1691.

[189] Chen J, Jiang L, Yu XH, et al. Endocan: a key player of cardiovascular disease. Front Cardiovasc Med. 2021; 8: 798699.

[190] Bechard D, Gentina T, Delehedde M, et al. Endocan is a novel chondroitin sulfate/dermatan sulfate proteoglycan that promotes hepatocyte growth factor/scatter factor mitogenic activity. J Biol Chem. 2001; 276(51): 48341-48349.

[191] Bian JS, Chen J, Zhang J, et al. ErbB3 governs endothelial dysfunction in hypoxia-induced pulmonary hypertension. Circulation. 2024.

[192] Wannamethee SG, Sattar N, Rumley A, et al. Tissue plasminogen activator, von Willebrand factor, and risk of type 2 diabetes in older men. Diabetes Care. 2008; 31(5): 995-1000.

[193] Simon AB, Derella CC, Blackburn M, et al. Endogenous estradiol contributes to vascular endothelial dysfunction in premenopausal women with type 1 diabetes. Cardiovasc Diabetol. 2023; 22(1): 243.

[194] Desideri E, Ciccarone F, Ciriolo MR, Fratantonio D. Extracellular vesicles in endothelial cells: from mediators of cell-to-cell communication to cargo delivery tools. Free Radic Biol Med. 2021; 172: 508-520.

[195] Stepanian A, Bourguignat L, Hennou S, et al. Microparticle increase in severe obesity: not related to metabolic syndrome and unchanged after massive weight loss. Obesity (Silver Spring). 2013; 21(11): 2236-2243.

[196] Pichler HJ, Leichtle A, Stutz M, et al. Increased endothelial microparticles and oxidative stress at extreme altitude. Eur J Appl Physiol. 2016; 116(4): 739-748.

[197] Cardenas HL, Evanoff NG, Fandl HK, et al. Endothelial-derived extracellular vesicles associated with electronic cigarette use impair cerebral microvascular cell function. J Appl Physiol (1985). 2023; 135(2): 271-278.

[198] Osman A, El-Gamal H, Pasha M, et al. Endoplasmic reticulum (ER) stress-generated extracellular vesicles (microparticles) self-perpetuate ER stress and mediate endothelial cell dysfunction independently of cell survival. Front Cardiovasc Med. 2020; 7: 584791.

[199] Li B, Huang Q, Lin C, et al. Increased circulating CD31+/CD42b-EMPs in Perthes disease and inhibit HUVECs angiogenesis via endothelial dysfunction. Life Sci. 2021; 265: 118749.

[200] Heiss C, Amabile N, Lee AC, et al. Brief secondhand smoke exposure depresses endothelial progenitor cells activity and endothelial function: sustained vascular injury and blunted nitric oxide production. J Am Coll Cardiol. 2008; 51(18): 1760-1771.

[201] Fluitt MB, Kumari N, Nunlee-Bland G, Nekhai S, Gambhir KK. miRNA-15a, miRNA-15b, and miRNA-499 are reduced in erythrocytes of pre-diabetic African-American adults. Jacobs J Diabetes Endocrinol. 2016; 2(1).

[202] Zampetaki A, Kiechl S, Drozdov I, et al. Plasma microRNA profiling reveals loss of endothelial miR-126 and other microRNAs in type 2 diabetes. Circ Res. 2010; 107(6): 810-817.

[203] Zheng Y, Liu Y, Wang L, et al. MicroRNA-126 suppresses the proliferation and migration of endothelial cells in experimental diabetic retinopathy by targeting polo-like kinase 4. Int J Mol Med. 2021; 47(1): 151-160.

[204] Mori MA, Ludwig RG, Garcia-Martin R, Brandao BB, Kahn CR. Extracellular miRNAs: from biomarkers to mediators of physiology and disease. Cell Metab. 2019; 30(4): 656-673.

[205] Xiong Y, Chen L, Yan C, et al. Circulating exosomal miR-20b-5p inhibition restores Wnt9b signaling and reverses diabetes-associated impaired wound healing. Small. 2020; 16(3): e1904044.

[206] Katayama M, Wiklander O, Fritz T, et al. Circulating exosomal miR-20b-5p is elevated in type 2 diabetes and could impair insulin action in human skeletal muscle. Diabetes. 2019; 68(3): 515-526.

[207] Venkat P, Cui C, Chopp M, et al. MiR-126 mediates brain endothelial cell exosome treatment-induced neurorestorative effects after stroke in type 2 diabetes mellitus mice. Stroke. 2019; 50(10): 2865-2874.

[208] Chiesa ST, Marcovecchio ML, Benitez-Aguirre P, et al. Vascular effects of ACE (angiotensin-converting enzyme) inhibitors and statins in adolescents with type 1 diabetes. Hypertension. 2020; 76(6): 1734-1743.

[209] Craighead DH, Heinbockel TC, Freeberg KA, et al. Time-efficient inspiratory muscle strength training lowers blood pressure and improves endothelial function, NO bioavailability, and oxidative stress in midlife/older adults with above-normal blood pressure. J Am Heart Assoc. 2021; 10(13): e020980.

[210] Yubero-Serrano EM, Fernandez-Gandara C, Garcia-Rios A, et al. Mediterranean diet and endothelial function in patients with coronary heart disease: an analysis of the CORDIOPREV randomized controlled trial. PLoS Med. 2020; 17(9): e1003282.

[211] Vamvakis A, Gkaliagkousi E, Lazaridis A, et al. Impact of intensive lifestyle treatment (Diet Plus Exercise) on endothelial and vascular function, arterial stiffness and blood pressure in stage 1 hypertension: results of the HINTreat randomized controlled trial. Nutrients. 2020; 12(5).

[212] Wood E, Hein S, Mesnage R, et al. Wild blueberry (poly)phenols can improve vascular function and cognitive performance in healthy older individuals: a double-blind randomized controlled trial. Am J Clin Nutr. 2023; 117(6): 1306-1319.

[213] Jeong JH, Lee N, Tucker MA, et al. Tetrahydrobiopterin improves endothelial function in patients with cystic fibrosis. J Appl Physiol (1985). 2019; 126(1): 60-66.

[214] Oliveira A, Arismendi MI, Machado L, Sato EI. Ramipril improves endothelial function and increases the number of endothelial progenitor cells in patients with systemic lupus erythematosus. J Clin Rheumatol. 2022; 28(7): 349-353.

[215] Rexhaj E, Bar S, Soria R, et al. Effects of alirocumab on endothelial function and coronary atherosclerosis in myocardial infarction: A PACMAN-AMI randomized clinical trial substudy. Atherosclerosis. 2024; 392: 117504.

[216] Honda A, Tahara N, Tahara A, et al. Effects of olmesartan and amlodipine on blood pressure, endothelial function, and vascular inflammation. J NuclCardiol. 2023; 30(4): 1613-1626.

[217] Gao J, Pan X, Li G, Chatterjee E, Xiao J. Physical exercise protects against endothelial dysfunction in cardiovascular and metabolic diseases. J Cardiovasc Transl Res. 2022; 15(3): 604-620.

[218] Yang H, Song L, Ning X, et al. Enhanced external counterpulsation ameliorates endothelial dysfunction and elevates exercise tolerance in patients with coronary artery disease. Front Cardiovasc Med. 2022; 9: 997109.

[219] Wienbergen H, Hambrecht R. Physical exercise and its effects on coronary artery disease. Curr OpinPharmacol. 2013; 13(2): 218-225.

[220] Mavri A, Poredos P, Suran D, et al. Effect of diet-induced weight loss on endothelial dysfunction: early improvement after the first week of dieting. Heart Vessels. 2011; 26(1): 31-38.

[221] Ma L, Li K, Wei W, et al. Exercise protects aged mice against coronary endothelial senescence via FUNDC1-dependent mitophagy. Redox Biol. 2023; 62: 102693.

[222] Sacks FM, Lichtenstein AH, Wu J, et al. Dietary fats and cardiovascular disease: a presidential advisory from the American Heart Association. Circulation. 2017; 136(3): e1-e23.

[223] DeSalvo KB, Olson R, Casavale KO. Dietary guidelines for Americans. JAMA. 2016; 315(5): 457-458.

[224] Eleftheriou D, Benetou V, Trichopoulou A, La Vecchia C, Bamia C. Mediterranean diet and its components in relation to all-cause mortality: meta-analysis. Br J Nutr. 2018; 120(10): 1081-1097.

[225] Davis CR, Hodgson JM, Woodman R, et al. A Mediterranean diet lowers blood pressure and improves endothelial function: results from the MedLey randomized intervention trial. Am J Clin Nutr. 2017; 105(6): 1305-1313.

[226] Schwingshackl L, Morze J, Hoffmann G. Mediterranean diet and health status: active ingredients and pharmacological mechanisms. Br J Pharmacol. 2020; 177(6): 1241-1257.

[227] Ferrari R, Guardigli G, Ceconi C. Secondary prevention of CAD with ACE inhibitors: a struggle between life and death of the endothelium. Cardiovasc Drugs Ther. 2010; 24(4): 331-339.

[228] Lazar HL, Bao Y, Rivers S, Colton T, Bernard SA. High tissue affinity angiotensin-converting enzyme inhibitors improve endothelial function and reduce infarct size. Ann Thorac Surg. 2001; 72(2): 548-553; discussion 553–4.

[229] Tehrani AY, White Z, Tung LW, et al. Pleiotropic activation of endothelial function by angiotensin II receptor blockers is crucial to their protective anti-vascular remodeling effects. Sci Rep. 2022; 12(1): 9771.

[230] Carucci L, Bova M, Petraroli A, et al. Angiotensin-converting enzyme inhibitor-associated angioedema: from bed to bench. J InvestigAllergol Clin Immunol. 2020; 30(4): 272-280.

[231] Sola S, Mir MQ, Cheema FA, et al. Irbesartan and lipoic acid improve endothelial function and reduce markers of inflammation in the metabolic syndrome: results of the Irbesartan and Lipoic Acid in Endothelial Dysfunction (ISLAND) study. Circulation. 2005; 111(3): 343-348.

[232] Maffei A, Lembo G. Nitric oxide mechanisms of nebivolol. Ther Adv Cardiovasc Dis. 2009; 3(4): 317-327.

[233] Altun I, Oz F, Arkaya SC, et al. Effect of statins on endothelial function in patients with acute coronary syndrome: a prospective study using adhesion molecules and flow-mediated dilatation. J Clin Med Res. 2014; 6(5): 354-361.

[234] Zaric B, Obradovic M, Trpkovic A, et al. Endothelial dysfunction in dyslipidaemia: molecular mechanisms and clinical implications. Curr Med Chem. 2020; 27(7): 1021-1040.

[235] Katsiki N, Mikhailidis DP, Banach M. Effects of statin treatment on endothelial function, oxidative stress and inflammation in patients with arterial hypertension and normal cholesterol levels. J Hypertens. 2011; 29(12): 2493-2494; author reply 2494.

[236] Reriani MK, Dunlay SM, Gupta B, et al. Effects of statins on coronary and peripheral endothelial function in humans: a systematic review and meta-analysis of randomized controlled trials. Eur J Cardiovasc Prev Rehabil. 2011; 18(5): 704-716.

[237] Motoji Y, Fukazawa R, Matsui R, et al. Statins show anti-atherosclerotic effects by improving endothelial cell function in a kawasaki disease-like vasculitis mouse model. Int J Mol Sci. 2022; 23(24).

[238] Qazi SU, Qamar U, Maqsood MT, et al. Efficacy of allopurinol in improving endothelial dysfunction: a systematic review and meta-analysis. High Blood Press Cardiovasc Prev. 2023; 30(6): 539-550.

[239] Hajizadeh-Sharafabad F, Sharifi ZE. Role of alpha-lipoic acid in vascular function: a systematic review of human intervention studies. Crit Rev Food Sci Nutr. 2022; 62(11): 2928-2941.

[240] Bueno-Pereira TO, Bertozzi-Matheus M, Zampieri GM, et al. Markers of endothelial dysfunction are attenuated by resveratrol in preeclampsia. Antioxidants (Basel). 2022; 11(11).

[241] Sha W, Zhao B, Wei H, et al. Astragalus polysaccharide ameliorates vascular endothelial dysfunction by stimulating macrophage M2 polarization via potentiating Nrf2/HO-1 signaling pathway. Phytomedicine. 2023; 112: 154667.

[242] Wang HJ, Ran HF, Yin Y, et al. Catalpol improves impaired neurovascular unit in ischemic stroke rats via enhancing VEGF-PI3K/AKT and VEGF-MEK1/2/ERK1/2 signaling. Acta Pharmacol Sin. 2022; 43(7): 1670-1685.

[243] Sandoo A, van Zanten JJ, Metsios GS, Carroll D, Kitas GD. The endothelium and its role in regulating vascular tone. Open Cardiovasc Med J. 2010; 4: 302-312.

[244] Ludmer PL, Selwyn AP, Shook TL, et al. Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary arteries. N Engl J Med. 1986; 315(17): 1046-1051.

[245] Niccoli G, Scalone G, Crea F. Coronary functional tests in the catheterization laboratory - pathophysiological and clinical relevance. Circ J. 2015; 79(4): 676-684.

[246] Minhas AS, Goerlich E, Corretti MC, et al. Imaging assessment of endothelial function: an index of cardiovascular health. Front Cardiovasc Med. 2022; 9: 778762.

[247] Flammer AJ, Anderson T, Celermajer DS, et al. The assessment of endothelial function: from research into clinical practice. Circulation. 2012; 126(6): 753-767.

[248] Lyngbakken MN, Myhre PL, Rosjo H, Omland T. Novel biomarkers of cardiovascular disease: applications in clinical practice. Crit Rev Clin Lab Sci. 2019; 56(1): 33-60.

[249] Antoniades C, Demosthenous M, Tousoulis D, et al. Role of asymmetrical dimethylarginine in inflammation-induced endothelial dysfunction in human atherosclerosis. Hypertension. 2011; 58(1): 93-98.

[250] Kharbanda RK, Walton B, Allen M, et al. Prevention of inflammation-induced endothelial dysfunction: a novel vasculo-protective action of aspirin. Circulation. 2002; 105(22): 2600-2604.

[251] Semaan HB, Gurbel PA, Anderson JL, et al. The effect of chronic azithromycin therapy on soluble endothelium-derived adhesion molecules in patients with coronary artery disease. J Cardiovasc Pharmacol. 2000; 36(4): 533-537.

[252] Nozaki T, Sugiyama S, Koga H, et al. Significance of a multiple biomarkers strategy including endothelial dysfunction to improve risk stratification for cardiovascular events in patients at high risk for coronary heart disease. J Am Coll Cardiol. 2009; 54(7): 601-608.

[253] Blann AD. A reliable marker of vascular function: Does it exist? Trends Cardiovasc Med. 2015; 25(7): 588-591.

[254] Yamamoto E, Sugiyama S, Hirata Y, et al. Prognostic significance of circulating leukocyte subtype counts in patients with coronary artery disease. Atherosclerosis. 2016; 255: 210-216.

[255] Urbanski K, Ludew D, Filip G, et al. CD14(+)CD16(++) “nonclassical” monocytes are associated with endothelial dysfunction in patients with coronary artery disease. ThrombHaemost. 2017; 117(5): 971-980.

[256] Arnold KA, Blair JE, Paul JD, et al. Monocyte and macrophage subtypes as paired cell biomarkers for coronary artery disease. Exp Physiol. 2019; 104(9): 1343-1352.

[257] Fadaei R, Shateri H, DiStefano JK, et al. Higher circulating levels of ANGPTL8 are associated with body mass index, triglycerides, and endothelial dysfunction in patients with coronary artery disease. Mol Cell Biochem. 2020; 469(1-2): 29-39.

[258] Deng J, Qian X, Li J, et al. Evaluation of serum cysteine-rich protein 61 levels in patients with coronary artery disease. Biomark Med. 2018; 12(4): 329-339.

[259] Moradi N, Fadaei R, Emamgholipour S, et al. Association of circulating CTRP9 with soluble adhesion molecules and inflammatory markers in patients with type 2 diabetes mellitus and coronary artery disease. PLoS One. 2018; 13(1): e0192159.

[260] Yin C, Hu W, Wang M, et al. Irisin as a mediator between obesity and vascular inflammation in Chinese children and adolescents. NutrMetab Cardiovasc Dis. 2020; 30(2): 320-329.

[261] Huerta-Delgado AS, Roffe-Vazquez DN, Gonzalez-Gil AM, et al. Serum irisin levels, endothelial dysfunction, and inflammation in pediatric patients with type 2 diabetes mellitus and metabolic syndrome. J Diabetes Res. 2020; 2020: 1949415.

[262] Guo W, Zhang B, Wang X. Lower irisin levels in coronary artery disease: a meta-analysis. Minerva Endocrinol. 2020; 45(1): 61-69.

[263] Safdar B, Guo X, Johnson C, et al. Elevated renalase levels in patients with acute coronary microvascular dysfunction - a possible biomarker for ischemia. Int J Cardiol. 2019; 279: 155-161.

[264] Nozue T, Hattori H, Ogawa K, et al. Effects of statin therapy on plasma proprotein convertase subtilisin/kexin type 9 and sortilin levels in statin-naive patients with coronary artery disease. J AtherosclerThromb. 2016; 23(7): 848-856.

[265] Caselli C, Del TS, Ragusa R, et al. Association of PCSK9 plasma levels with metabolic patterns and coronary atherosclerosis in patients with stable angina. Cardiovasc Diabetol. 2019; 18(1): 144.

[266] Paapstel K, Kals J, Eha J, et al. Inverse relations of serum phosphatidylcholines and lysophosphatidylcholineswith vascular damage and heart rate in patients with atherosclerosis. NutrMetab Cardiovasc Dis. 2018; 28(1): 44-52.

[267] Zhang Y, Zhang L, Wang Y, et al. KCNQ1OT1, HIF1A-AS2 and APOA1-AS are promising novel biomarkers for diagnosis of coronary artery disease. Clin Exp Pharmacol Physiol. 2019; 46(7): 635-642.

[268] Reddy LL, Shah S, Ponde CK, Rajani RM, Ashavaid TF. Circulating miRNA-33: a potential biomarker in patients with coronary artery disease. Biomarkers. 2019; 24(1): 36-42.

[269] Wang W, Li Z, Zheng Y, et al. Circulating microRNA-92a level predicts acute coronary syndrome in diabetic patients with coronary heart disease. Lipids Health Dis. 2019; 18(1): 22.

[270] Horvath M, Horvathova V, Hajek P, et al. MicroRNA-331 and microRNA-151-3p as biomarkers in patients with ST-segment elevation myocardial infarction. Sci Rep. 2020; 10(1): 5845.

[271] Ling H, Guo Z, Shi Y, Zhang L, Song C. Serum exosomal microRNA-21, microRNA-126, and PTEN are novel biomarkers for diagnosis of acute coronary syndrome. Front Physiol. 2020; 11: 654.

[272] Wu S, Sun H, Sun B. MicroRNA-145 is involved in endothelial cell dysfunction and acts as a promising biomarker of acute coronary syndrome. Eur J Med Res. 2020; 25(1): 2.

[273] Chen T, Wang ZY, Li CC. miRNA-22 as a candidate diagnostic biomarker for coronary slow flow. Cardiol Res Pract. 2020; 2020: 7490942.

[274] Danaii S, Shiri S, Dolati S, et al. The Association between inflammatory cytokines and miRNAs with slow coronary flow phenomenon. Iran J Allergy Asthma Immunol. 2020; 19(1): 56-64.

[275] Chen LW, Tsai MC, Chern CY, et al. A chalcone derivative, 1m-6, exhibits atheroprotective effects by increasing cholesterol efflux and reducing inflammation-induced endothelial dysfunction. Br J Pharmacol. 2020; 177(23): 5375-5392.

[276] Zhong M, Zhang X, Shi X, Zheng C. Halofuginone inhibits LPS-induced attachment of monocytes to HUVECs. Int Immunopharmacol. 2020; 87: 106753.

[277] Xu S, Kamato D, Little PJ, et al. Targeting epigenetics and non-coding RNAs in atherosclerosis: from mechanisms to therapeutics. Pharmacol Ther. 2019; 196: 15-43.

[278] Borck PC, Guo LW, Plutzky J. BET epigenetic reader proteins in cardiovascular transcriptional programs. Circ Res. 2020; 126(9): 1190-1208.

[279] Winkels H, Ehinger E, Vassallo M, et al. Atlas of the immune cell repertoire in mouse atherosclerosis defined by single-cell RNA-sequencing and mass cytometry. Circ Res. 2018; 122(12): 1675-1688.

[280] Fernandez DM, Rahman AH, Fernandez NF, et al. Single-cell immune landscape of human atherosclerotic plaques. Nat Med. 2019; 25(10): 1576-1588.

[281] Williams JW, Winkels H, Durant CP, et al. Single cell RNA sequencing in atherosclerosis research. Circ Res. 2020; 126(9): 1112-1126.

[282] Kalucka J, de Rooij L, Goveia J, et al. Single-cell transcriptome atlas of murine endothelial cells. Cell. 2020; 180(4): 764-779. e20.

[283] Rohlenova K, Goveia J, Garcia-Caballero M, et al. Single-cell RNA sequencing maps endothelial metabolic plasticity in pathological angiogenesis. Cell Metab. 2020; 31(4): 862-877. e14.

[284] Andueza A, Kumar S, Kim J, et al. Endothelial reprogramming by disturbed flow revealed by single-cell RNA and chromatin accessibility study. Cell Rep. 2020; 33(11): 108491.

[285] Linna-Kuosmanen S, Tomas BV, Moreau PR, et al. NRF2 is a key regulator of endothelial microRNA expression under proatherogenic stimuli. Cardiovasc Res. 2021; 117(5): 1339-1357.

[286] Schnitzler JG, Hoogeveen RM, Ali L, et al. Atherogenic lipoprotein(a) increases vascular glycolysis, thereby facilitating inflammation and leukocyte extravasation. Circ Res. 2020; 126(10): 1346-1359.

[287] Sabbatinelli J, Prattichizzo F, Olivieri F, et al. Where metabolism meets senescence: focus on endothelial cells. Front Physiol. 2019; 10: 1523.

RIGHTS & PERMISSIONS

2024 The Author(s). MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.