Endothelial Dysfunction in Human Disease
Abstract
The vascular endothelium plays a key role in the local regulation of vascular tone by the release of vasodilator substances (i.e. endothelium-derived relaxing factor (EDRF = nitric oxide, NO) and prostacyclin) and vasoconstrictor substances (i.e. thromboxane A2, free radicals, or endothelin). Using either agents like acetylcholine or changes in flow to stimulate the release of EDRF (NO), clinical studies have revealed the importance of EDRF in both basal and stimulated control of vascular tone in large epicardial coronary arteries and in the coronary microcirculation. The regulatory function of the endothelium is altered by cardiovascular risk factors or disorders such as hypercholesterolemia, chronic smoking, hypertension or chronic heart failure. Endothelial dysfunction appears to have detrimental functional consequences as well as adverse longterm effects, including vascular remodelling. Endothelial dysfunction is associated with impaired tissue perfusion particularly during stress and paradoxical vasoconstriction of large conduit vessels including the coronary arteries. These effects may cause or contribute to myocardial ischemia. Several mechanisms may be involved in the development of endothelial dysfunction, such as reduced synthesis and release of EDRF or enhanced inactivation of EDRF after its release from endothelial cells by radicals or oxidized low-density lipoprotein (LDL). Increased plasma levels of oxidized LDL have been noted in chronic smokers and are related to the extent endothelial dysfunction, raising the possibility that chronic smoking potentiates endothelial dysfunction by increasing circulating and tissue levels of oxidized LDL. In heart failure, cytokines and/or reduced flow (reflecting reduced shear stress) may be involved in the development of endothelial dysfunction and can be reversed by physical training. Other mechanisms include an activated renin-angiotensin system (i.e. postmyocardial infarction) with increased breakdown of bradykinin by enhanced angiotensin converting enzyme (ACE) activity. There is evidence that endogenous bradykinin is involved in coronary vasomotor control both in coronary conduit and resistance vessels. ACE inhibitors enhance endothelial function by a bradykinin-dependent mechanism and probably also by blunting the generation of superoxide anion. Endothelial dysfunction appears to be reversible by administering L-arginine, the precursor of nitric oxide, lowering cholesterol levels, physical training, antioxidants such as vitamin C, or ACE inhibition.
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A few studies have found that dietary nitrate inhibits platelet aggregation.
“A few studies have found inhibitory effects of dietary nitrate on platelet aggregation, suggesting that inhibition of abnormal platelet aggregation may be partly responsible for the cardiovascular benefits of nitrate supplementation.”
From The effects of dietary nitrate on blood pressure and endothelial function: a review of human intervention studies (2013) · cites this paper as [106]
Richardson et al. (106) demonstrated that a single 2 mmol bolus of potassium nitrate inhibited platelet aggregation by up to 31 % in healthy individuals.
“For example, Richardson et al. (106) demonstrated that a single 2 mmol bolus of potassium nitrate inhibited platelet aggregation by up to 31 % in healthy individuals.”
From The effects of dietary nitrate on blood pressure and endothelial function: a review of human intervention studies (2013) · cites this paper as [106]
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Damy, T., Ratajczak, P., Robidel, E., Bendall, J. K., Oliviéro, P., Boczkowski, J., Ebrahimian, T., Marotte, F., Samuel, J., & Heymes, C. (2003) · The FASEB Journal · doi:10.1096/fj.02-1208fje · Cited by 115 · see citing works
“In addition, according to data obtained in dogs (29) and humans (30, 31), our findings indicate that NOS3 expression and activity decrease after MI in senescent hearts.”
BackgroundEndothelial cell dysfunction: can’t live with it, how to live without it
Goligorsky, M. S. (2005) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00333.2004 · Cited by 116 · see citing works
α-lactorphin and β-lactorphin improve arterial function in spontaneously hypertensive rats
Sipola, M., Finckenberg, P., Vapaatalo, H., Pihlanto-Leppälä, A., Korhonen, H. J. T., Korpela, R., & Nurminen, M. (2002) · Life Sciences · doi:10.1016/s0024-3205(02)01793-9 · Cited by 114 · see citing works
Duscha, B. D., Schulze, P. C., Robbins, J. L., & Forman, D. E. (2007) · Heart Failure Reviews · doi:10.1007/s10741-007-9056-8 · Cited by 113 · see citing works
“Two powerful vasoconstrictors, angiotensin II and endothelin1, are elevated in patients with CHF, which further contribute to the abnormal regulation of vascular tone [30–32].”
BackgroundThe Role of the Transcription Factor KLF2 in Vascular Development and Disease
Novodvorský, P., & Chico, T. (2014) · Progress in molecular biology and translational science · doi:10.1016/b978-0-12-386930-2.00007-0 · Cited by 114 · see citing works
Hobbs, D. A., George, T. W., & Lovegrove, J. A. (2013) · Nutrition Research Reviews · doi:10.1017/s0954422413000188 · Cited by 114 · see citing works
“Endothelial dysfunction is broadly characterised as an imbalance between the release of vasoconstrictors and vasodilators, which is initiated by damage or impairment of the endothelial cell layer((70)).”
BackgroundKocaman, O., Oflaz, H., Yekeler, E., Dursun, M., Erdoğan, D., Demirel, Ş., Alışır, S., Turgut, F. H., Mercanoğlu, F., & Ecder, T. (2004) · American Journal of Kidney Diseases · doi:10.1053/j.ajkd.2004.01.011 · Cited by 112 · see citing works
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“Normal endothelial function is maintained by a balance of oxidative stress and nitric oxide (NO).(4,5) One mechanism of endothelial dysfunction is an increase in oxidative stress, which inactivates NO.”
BackgroundBhidayasiri, R., & Truong, D. D. (2004) · Postgraduate Medical Journal · doi:10.1136/pgmj.2004.019356 · Cited by 110 · see citing works
Nitrotyrosine Causes Selective Vascular Endothelial Dysfunction and DNA Damage
Mihm, M. J., Liang, J., & Bauer, J. A. (2000) · Journal of Cardiovascular Pharmacology · doi:10.1097/00005344-200008000-00007 · Cited by 107 · see citing works
Tousoulis, D., Antoniades, C. A., Vassiliadou, C., Toutouza, M., Pitsavos, C. E., Tentolouris, C. A., Trikas, A. G., & Stefanadis, C. (2005) · European Journal of Heart Failure · doi:10.1016/j.ejheart.2005.03.007 · Cited by 106 · see citing works
“Heart failure is associated with endothelial dysfunction, which may be the result of a variety of mechanisms, such as the increased levels of cytokines (i.e. tumor necrosis alpha (TNF-a)) impairing the expression of NO-synthase [30], impaired endothelial–receptor–signal transduction pathways and increased angiotensin-…”
BackgroundGhosh, P., Bitsanis, D., Ghebremeskel, K., Crawford, M. A., & Poston, L. (2001) · The Journal of Physiology · doi:10.1111/j.1469-7793.2001.00815.x · Cited by 105 · see citing works
“Poor endothelium-dependent relaxation in response to acetylcholine is associated with a range of cardiovascular disorders (Drexler & Hornig, 1999), and has been proposed to be a primary event in the aetiology of atherosclerosis.”
BackgroundAdapala, R. K., Talasila, P. K., Bratz, I. N., Zhang, D. X., Suzuki, M., Meszaros, J. G., & Thodeti, C. K. (2011) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00142.2011 · Cited by 104 · see citing works
Bunte, M. C., Patnaik, M. M., PRITZKER, M. R., & Burns, L. J. (2008) · Bone Marrow Transplantation · doi:10.1038/sj.bmt.1705990 · Cited by 101 · see citing works
Peña-Jorquera, H., Cid-Jofré, V., Landaeta-Díaz, L., Petermann-Rocha, F., Martorell, M., Zbinden-Foncea, H., Ferrari, G., Jorquera-Aguilera, C., & Cristi-Montero, C. (2023) · Nutrients · doi:10.3390/nu15143244 · Cited by 103 · see citing works
“Interestedly, the magnitude of this positive effect observed with a high-flavanol cocoa drink was similar to that observed in a long-term pharmacological approach with statins [123,124].”
ResultTateshima, S., Murayama, Y., Villablanca, J. P., Morino, T., Takahashi, H., Yamauchi, T., Tanishita, K., & Viñuela, F. (2001) · Journal of neurosurgery · doi:10.3171/jns.2001.95.6.1020 · Cited by 102 · see citing works
Poitras, V. J., & Pyke, K. E. (2013) · International Journal of Psychophysiology · doi:10.1016/j.ijpsycho.2013.03.019 · Cited by 102 · see citing works
Chrapko, W. E., Jurasz, P., Radomski, M. W., Archer, S. L., Newman, S. C., Baker, G. B., Lara, N., & Mellédo, J. L. (2005) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300961 · Cited by 97 · see citing works
“Finkel et al (1996) found that in subjects with ischemic heart disease being treated for MD, the SSRI paroxetine reduced levels of NO, suggesting a potentially deleterious effect of paroxetine on the CV system since decreased endothelium production of NO is usually associated with increased CV risk (Drexler and Hornig…”
BackgroundAnker, S. D., Clark, A. L., Winkler, R., Zugck, C., Cicoira, M., Ponikowski, P. P., Davos, C. H., Banasiak, W., Zardini, P., Haass, M., et al. (2006) · International Journal of Cardiology · doi:10.1016/j.ijcard.2006.03.057 · Cited by 97 · see citing works
Neckář, J. (2002) · Cardiovascular Research · doi:10.1016/s0008-6363(02)00456-x · Cited by 93 · see citing works
Neutrophil activation and production of reactive oxygen species in pre-eclampsia
Lee, V. M., Quinn, P. A., Jennings, S. C., & Ng, L. L. (2003) · Journal of Hypertension · doi:10.1097/00004872-200302000-00032 · Cited by 92 · see citing works
Trends of tea in cardiovascular health and disease: A critical review
Fang, J., Sureda, A., Sanches-Silva, A. T., Khan, F., Xu, S., & Nabavi, S. M. (2019) · Trends in Food Science & Technology · doi:10.1016/j.tifs.2019.04.001 · Cited by 91 · see citing works
Rossi, G. P., Seccia, T. M., & Nussdorfer, G. G. (2001) · International review of cytology · doi:10.1016/s0074-7696(01)09014-3 · Cited by 91 · see citing works
Distinct Effects of Naringenin and Hesperetin on Nitric Oxide Production from Endothelial Cells
Liu, L., Xu, D., & Cheng, Y. (2008) · Journal of Agricultural and Food Chemistry · doi:10.1021/jf0723007 · Cited by 90 · see citing works
Vascular Reactivity in Hypogonadal Men Is Reduced by Androgen Substitution
Zitzmann, M., Brune, M., & Nieschlag, E. (2002) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2002-020504 · Cited by 86 · see citing works
- Authors
- Drexler, H., & Hornig, B.
- Affiliations
- Medizinische Hochschule Hannover (DE)
- Venue
- Journal of Molecular and Cellular Cardiology
- Publisher
- Elsevier BV
- Published
- 1999-01
- Volume
- 31
- Issue
- 1
- Pages
- 51-60
- ISSN
- 0022-2828 (ISSN-L)
- OpenAlex
- W2074957886
- Cited by
- 471
- References
- 0
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 3 · 2023: 5 · 2022: 8 · 2021: 4 · 2020: 7 · 2019: 11 · 2018: 4 · 2017: 7 · 2016: 14 · 2015: 11 · 2014: 18 · 2013: 23 · 2012: 19
- FWCI
- 16.77
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Molecular and Cellular Cardiology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Eicosanoids and Hypertension Pharmacology
- Keywords
- endothelial dysfunction, nitric oxide, endothelium-derived relaxing factor, coronary microcirculation, oxidized LDL, chronic smoking, heart failure, renin-angiotensin system, bradykinin, ACE inhibitors, L-arginine, exercise training, antioxidants, myocardial ischemia, vascular remodeling, shear stress, hypertension, hypercholesterolemia
- MeSH terms
- Acetylcholine, Ascorbic Acid, Cardiac Output, Low, Coronary Disease, Dose-Response Relationship, Drug, Endothelium, Vascular, Enzyme Inhibitors, Humans, Hypercholesterolemia, Hyperemia, Lipoproteins, LDL, Radial Artery, omega-N-Methylarginine
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