In human vascular diseases, endothelial dysfunction is a systemic pathological state of the endothelium (the inner lining of blood vessels) and can be broadly defined as an imbalance between vasodilating and vasoconstricting substances produced by (or acting on) the endothelium. Normal functions of endothelial cells include mediation of coagulation, platelet adhesion, immune function and control of volume and electrolyte content of the intravascular and extravascular spaces.
Endothelial dysfunction can result from and/or contribute to several disease processes, as occurs in hypertension, hypercholesterolaemia, diabetes, septic shock, and Behcet's disease, and it can also result from environmental factors, such as from smoking tobacco products and exposure to air pollution. Endothelial dysfunction is more prevalent in shift workers, a group known to have a higher risk for cardiovascular diseases. Most of these studies on human participants have involved the percentage flow-mediated dilation (FMD%) index as the study outcome, which must have proper statistical consideration to be interpreted correctly. Endothelial dysfunction is a major physiopathological mechanism that leads towards coronary artery disease, and other atherosclerotic diseases.
The epidemiology of endothelial dysfunction is unknown, as %FMD varies with baseline artery diameter. This can make cross-sectional comparisons of FMD% difficult. Endothelial dysfunction was found in approximately half of women with chest pain, in the absence of overt blockages in large coronary arteries. This endothelial dysfunction cannot be predicted by typical risk factors for atherosclerosis (e.g., obesity, cholesterol, smoking) and hormones.
Endothelial Dysfunction and Atherosclerosis Link
Endothelial dysfunction is thought to be a key event in the development of atherosclerosis and has been reported to predate clinically obvious vascular pathology by many years. However, the problem with this assertion in terms of the flow-mediated response indicator of endothelial dysfunction is that a morphological characteristic of atherosclerosis (baseline artery size) is inherent in the calculation of percentage flow-mediated dilation. Endothelial dysfunction is associated with reduced anticoagulant properties as well as increased adhesion molecule expression, chemokine and other cytokine release, as well as reactive oxygen species production from the endothelium. This leads to inflammation and myofibroblast migration and proliferation inside the vessel all of which play important roles in the development of atherosclerosis.
In fact, endothelial dysfunction has been shown to be of prognostic significance in predicting independently vascular events including stroke and myocardial infarction. However, again so has baseline artery size which happens to be part of the calculation of percentage flow-mediated dilation (%FMD). Endothelial function testing might have potential prognostic value for the early detection of cardiovascular disease; clinical trials in the recent years have demonstrated the feasibility of translating this measurement to the clinical practice. However, the baseline artery size component of percentage flow-mediated dilation may also be just as prognostic and is easier to measure reliabily than flow-mediated dilation.
Nitric Oxide bioavailability reduction in Endothelial Dysfunction
Nitric Oxide (NO) reduction is considered the hallmark of endothelial dysfunction   A key and quantifiable feature of endothelial dysfunction is the inability of arteries and arterioles to dilate fully in response to an appropriate stimulus that stimulates release of vasodilators from the endothelium like NO. Endothelial dysfunction is commonly associated with decreased NO bioavailability, which is due to impaired NO production by the endothelium and/or increased inactivation of NO by reactive oxygen species.
This can be tested by a variety of methods including iontophoresis of acetylcholine, direct administration of various vasoactive agents to segments of blood vessels, localised heating of the skin and temporary arterial occlusion by inflating a blood pressure cuff to high pressures. Testing can also take place in the coronary arteries themselves but this is invasive and not normally conducted unless there is a clinical reason for intracoronary catheterisation.
Of all the current tests employed in the research setting, flow-mediated dilation is the most widely used non-invasive test for assessing endothelial function. This technique measures endothelial function by inducing reactive hyperemia via temporary arterial occlusion and measuring the resultant relative increase in blood vessel diameter via ultrasound. Measurement of endothelial function by Peripheral arterial tonometry or endopat, is also mediated by a NO response. As people with endothelial dysfunction have low NO bioavailability, their blood vessels have a decreased capacity to dilate in response to certain stimuli, compared to those with normal endothelial function. In order to properly perform a test for endothelial dysfunction, patients must avoid having certain medications and food at least 12 hours prior to the test; temperature must be controlled (at room temperature) , and ideally should be performed at the same time in the same patient due to circadian rhythms.
NO has the following physiological effects that contribute to the inhibition of atherosclerosis: 1) NO is released and produces vasodilation after shear stress in the vessel; the vasodilation NO mediated-response in turns decreases the shear stress. If the shear stress is chronically induced it leads to the upregulation of and release of inflammatory cytokines  2) NO decreases LDL oxidation; 3) NO reduces platelet aggregation to the endothelium 4) NO Inhibits smooth muscle cell proliferation 5) NO prevents leukocyte adhesion and infiltration into the vessel.
Testing & Diagnosis
The gold standard for measuring endothelial function is angiography with acetylcholine injection, however due to the invasive and complex nature of the procedure it has never been used outside research.
A noninvasive method to measure endothelial dysfunction is % Flow Mediated Dilation (FMD) as measured by Brachial Artery Ultrasound Imaging (BAUI). Current measurements of endothelial function via FMD vary due to technical and physiological factors. A negative correlation between percent flow mediated dilation and baseline artery size is recognised as a fundamental scaling problem, leading to biased estimates of endothelial function. For research on FMD an ANCOVA approach to adjusting FMD for variation in baseline diameter is more appropriate. Another challenge of FMD is variability across centers and the requirement of highly qualified technicians to perform the procedure.
Non-invasive, FDA-approved devices for measuring Endothelial function that work by measuring Reactive Hyperemia Index (RHI) is Itamar Medical's EndoPAT,  has shown an 80% sensitivity and 86% specificity to diagnose coronary artery disease when compared against the gold standard, acetylcoline angiogram. This results suggests that this peripheral test reflects the physiology of the coronary endothelium. Endopat has been tested in several clinical trials at multiple centers (including major cohort studies such as the Framingham Heart Study, the Heart SCORE study, and the Gutenberg Health Study). The results from clinical trials have shown that Endopat is useful for risk evaluation, stratification and prognosis of getting major cardiovascular events (MACE).
Prevention and treatment
Endothelial function can be improved significantly by exercise, smoke cessation, weight loss in overweight or obese persons, and improved diet. Treatment of hypertension and hypercholesterolemia are also critical; the major pharmacological interventions to improve endothelial function in those set of patients are statins(HMGCoA-reductase inhibitor), and renin angiotensin system inhibitors, (such as ACE inhibitors and angiotensin II receptor antagonists). Some studies have found antioxidants, potassium and arginine supplementation to restore impaired endothelial function. A positive relationship exists between the consumption of trans fat (commonly found in hydrogenated products such as margarine) and the development of endothelial dysfunction. New third-generation β-blockers and 5-phosphodiesterase inhibitors may affect endothelial function. New non-invasive strategies that measure endothelial function will prove critical to assess which set of patients are improving their endothelial function. Statins have major pleiotropic anti-inflammatory and anti-hypertensive effects besides the cholesterol reduction effect. This immunomodulatory effects of statins may explain why some patients improve their endothelial function with those drugs.
Relevant endothelial function molecular mediators:
- Nitric oxide
- endothelial nitric oxide synthase
- Endothelium-derived relaxing factor
Relevant endothelial function molecular pathways:
- Integrin network
- PI3K-AKT Network
Relevant biophysical endothelial function mediators:
- Endothelial shear stress
- Deanfield J, Donald A, Ferri C, Giannattasio C, Halcox J, Halligan S, Lerman A, Mancia G, Oliver JJ, Pessina AC, Rizzoni D, Rossi GP, Salvetti A, Schiffrin EL, Taddei S, Webb DJ (2005). "Endothelial function and dysfunction. Part I: Methodological issues for assessment in the different vascular beds: a statement by the Working Group on Endothelin and Endothelial Factors of the European Society of Hypertension". J Hypertens 23 (1): 7–17. doi:10.1097/00004872-200501000-00004. PMID 15643116.
- Münzel T1, Sinning C, Post F, Warnholtz A, Schulz E (2008). "Pathophysiology, diagnosis and prognostic implications of endothelial dysfunction". Annals of Medicine 40 (18382884): 180–196. doi:10.1080/07853890701854702. PMID 18382884.
- Suessenbacher A, Potocnik M, Dörler J, Fluckinger G, Wanitschek M, Pachinger O, Frick M, Alber HF. Comparison of peripheral endothelial function in shift versus nonshift workers. Am J Cardiol. 2011 Mar 15;107(6):945-8.
- Atkinson and Batterham, Atherosclerosis 2013.
- Flammer AJ, Anderson T, Celermajer DS, Creager MA, Deanfield J, Ganz P, Hamburg NM, Lüscher TF, Shechter M, Taddei S, Vita JA, Lerman A. The assessment of endothelial function: from research into clinical practice. Circulation. 2012 Aug 7;126(6):753-67.
- Reis SE, Holubkov R, Smith AJC, Kelsey SF, Sharaf BL, Reichek N, Rogers WJ, Merz NB, Sopko G, Pepine CJ, "Coronary microvascular dysfunction is highly prevalent in women with chest pain in the absence of coronary artery disease: Results from the NHLBI WISE Study," Am Heart J, V. 141, No. 5 (May 2001), pp. 735-741
- Eren E1, Yilmaz N, Aydin O (2013). "Functionally Defective High-Density Lipoprotein and Paraoxonase: A Couple for Endothelial Dysfunction in Atherosclerosis". CHOLESTEROL 2013 (792090). doi:10.1371/journal.pgen.1001150. PMC 3814057. PMID 24222847.
- Gokce N. Clinical assessment of endothelial function: ready for prime time? Circ Cardiovasc Imaging. 2011 Jul;4(4):348-50.
- Davignon J, Ganz P. Role of endothelial dysfunction in atherosclerosis. Circulation. 2004 Jun 15;109(23 Suppl 1):III27-32. Review.
- Nohria A, Gerhard-Herman M, Creager MA, Hurley S, Mitra D, Ganz P. Role of nitric oxide in the regulation of digital pulse volume amplitude in humans. J. Appl Physiol. 2006 Aug;101(2):545-8
- Shyy JY, Chien S. Role of integrins in endothelial mechanosensing of shear stress. Circ Res. 2002 Nov 1;91(9):769-75. Review
- Davignon J, Ganz P. Role of endothelial dysfunction in atherosclerosis. Circulation. 2004 Jun 15;109(23 Suppl 1):III27-32. Review
- Ludmer PL, Selwyn AP, Shook TL, Wayne RR, Mudge GH, Alexander RW, Ganz P. Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary arteries. N Engl J Med. 1986 Oct 23;315(17):1046-51
- Monnink SH, Tio RA, van Boven AJ, van Gilst WH, van Veldhuisen DJ. The role of coronary endothelial function testing in patients suspected for angina pectoris. Int J Cardiol. 2004 Aug;96(2):123-9.
- Peretz, Alon; Daniel F Leotta; Jeffrey H Sullivan; Carol A Trenga; Fiona N Sands; Mary R Aulet (2007). "Flow mediated dilation of the brachial artery: an investigation of methods requiring further standardization". BMC Cardiovascular Disorders 7 (11).
- Thijssen DH, Black MA, Pyke KE, Padilla J, Atkinson G, Harris RA, Parker B, Widlansky ME, Tschakovsky ME, Green DJ. Assessment of flow-mediated dilation in humans: a methodological and physiological guideline. Am J Physiol Heart Circ Physiol. 2011 Jan;300(1):H2-12
- Kuvin JT, Mammen A, Mooney P, Alsheikh-Ali AA, Karas RH. Assessment of peripheral vascular endothelial function in the ambulatory setting. Vasc Med. 2007 Feb;12(1):13-6.
- Axtell AL, Gomari FA, Cooke JP. Assessing endothelial vasodilator function with the Endo-PAT 2000. J Vis Exp. 2010 Oct 15;(44).
- Bonetti PO, Pumper GM, Higano ST, Holmes DR Jr, Kuvin JT, Lerman A. Noninvasive identification of patients with early coronary atherosclerosis by assessment of digital reactive hyperemia. J Am Coll Cardiol. 2004 Dec 7;44(11):2137-41.
- Hamburg NM, Keyes MJ, Larson MG, Vasan RS, Schnabel R, Pryde MM, Mitchell GF, Sheffy J, Vita JA, Benjamin EJ. Cross-sectional relations of digital vascular function to cardiovascular risk factors in the Framingham Heart Study. Circulation. 2008 May 13;117(19):2467-74.
- Mulukutla SR, Venkitachalam L, Bambs C, Kip KE, Aiyer A, Marroquin OC, Reis SE. Black race is associated with digital artery endothelial dysfunction: results from the Heart SCORE study. Eur Heart J. 2010 Nov;31(22):2808-15.
- Schnabel RB, Wild PS, Schulz A, Zeller T, Sinning CR, Wilde S, Kunde J, Lubos E, Lackner KJ, Warnholtz A, Gori T, Blankenberg S, Munzel T; Gutenberg Health Study Investigators. Multiple endothelial biomarkers and noninvasive vascular function in the general population: the Gutenberg Health Study. Hypertension. 2012 Aug;60(2):288-95.
- Kuvin JT, Patel AR, Sliney KA, Pandian NG, Sheffy J, Schnall RP, Karas RH, Udelson JE. Assessment of peripheral vascular endothelial function with finger arterial pulse wave amplitude. Am Heart J. 2003 Jul;146(1):168-74.
- Rubinshtein R, Kuvin JT, Soffler M, Lennon RJ, Lavi S, Nelson RE, Pumper GM,Lerman LO, Lerman A. Assessment of endothelial function by non-invasive peripheral arterial tonometry predicts late cardiovascular adverse events. Eur Heart J. 2010 May;31(9):1142-8
- Matsuzawa Y, Sugiyama S, Sugamura K, Nozaki T, Ohba K, Konishi M, Matsubara J, Sumida H, Kaikita K, Kojima S, Nagayoshi Y, Yamamuro M, Izumiya Y, Iwashita S, Matsui K, Jinnouchi H, Kimura K, Umemura S, Ogawa H. Digital assessment of endothelial function and ischemic heart disease in women. J Am Coll Cardiol. 2010 Apr 20;55(16):1688-96.
- Heffernan KS, Karas RH, Patvardhan EA, Jafri H, Kuvin JT. Peripheral arterial tonometry for risk stratification in men with coronary artery disease. Clin Cardiol. 2010 Feb;33(2):94-8.
- Akiyama E, Sugiyama S, Matsuzawa Y, Konishi M, Suzuki H, Nozaki T, Ohba K, Matsubara J, Maeda H, Horibata Y, Sakamoto K, Sugamura K, Yamamuro M, Sumida H, Kaikita K, Iwashita S, Matsui K, Kimura K, Umemura S, Ogawa H. Incremental prognostic significance of peripheral endothelial dysfunction in patients with heart failure with normal left ventricular ejection fraction. J Am Coll Cardiol. 2012 Oct 30;60(18):1778-86.
- Matsue Y, Suzuki M, Nagahori W, Ohno M, Matsumura A, Hashimoto Y, Yoshida K, Yoshida M. Endothelial dysfunction measured by peripheral arterial tonometry predicts prognosis in patients with heart failure with preserved ejection fraction. Int J Cardiol. 2012 Sep 26
- Ruilope LM, Redón J, Schmieder R. Cardiovascular risk reduction by reversing endothelial dysfunction: ARBs, ACE inhibitors, or both? Expectations from the ONTARGET Trial Programme. Vasc Health Risk Manag. 2007;3(1):1-9.
- Briasoulis A, Tousoulis D, Androulakis ES, Papageorgiou N, Latsios G, Stefanadis C. Endothelial dysfunction and atherosclerosis: focus on novel therapeutic approaches. Recent Pat Cardiovasc Drug Discov. 2012 Apr;7(1):21-32. Review.
- Potassium softens vascular endothelium and increases nitric oxide release H. Oberleithnera,1,C. Calliesa,K. Kusche-Vihroga,H. Schillersa,V. Shahina,C. Riethmüllera,G. A. MacGregorb anH. E. de Wardenerb+ Author Affiliations aInstitute of Physiology II, University of Münster, D-48149 Münster, Germany; and bBlood Pressure Unit, Department of Cardiac and Vascular Medicine, St. George's University of London, London SW17 ORE, United Kingdom Communicated by Gerhard Giebisch, Yale University School of Medicine, New Haven, CT, December 21, 2008 (received for review August 20, 2008)
- Lopez-Garcia E, Schulze MB, Meigs JB, Manson JE, Rifai N, Stampfer MJ, Willett WC, Hu FB, "Consumption of trans fatty acids is related to plasma biomarkers of inflammation and endothelial dysfunction", Journal of Nutrition, Mar 2005;135(3):562-6.
- Tomasoni L, Sitia S, Borghi C, Cicero AF, Ceconi C, Cecaro F, Morganti A, De Gennaro Colonna V, Guazzi M, Morricone L, Malavazos AE, Marino P, Cavallino C, Shoenfeld Y, Turiel M., "Effects of treatment strategy on endothelial function", Autoimmunity Review, 2010 Oct;9(12):840-4