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{{Short description|Impaired function of the inner lining of blood/lymph vessels}}
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.<ref name="PMID: 15643116">{{cite journal | author = 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 | title = 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 | journal = J Hypertens | volume = 23 | issue = 1 | pages = 7–17 | year = 2005 | month = | pmid = 15643116| doi = 10.1097/00004872-200501000-00004| url = }}</ref> 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.
{{more medical citations needed|date=April 2018}}
{{Technical|date=February 2022}}
[[File:Viruses-13-00029-g001.webp|thumb|Comparison of healthy vs. dysfunctional vascular endothelium]]


In [[vascular disease]]s, '''endothelial dysfunction''' is a systemic pathological state of the [[endothelium]]. The main cause of endothelial dysfunction is impaired bioavailability of [[nitric oxide]].<ref name="pmid31354915">{{cite journal | vauthors = Marchio P, Guerra-Ojeda S, Mauricio MD | title=Targeting Early Atherosclerosis: A Focus on Oxidative Stress and Inflammation | journal= [[List of Hindawi academic journals#O|Oxidative Medicine and Cellular Longevity]] | volume=2019 | pages=8563845 | year=2019 | doi= 10.1155/2019/8563845 | pmc=6636482 | pmid=31354915 | doi-access=free }}</ref>
Endothelial dysfunction can result from and/or contribute to several disease processes, as occurs in [[septic shock]], [[hypertension]], [[hypercholesterolaemia]], [[diabetes]],
[[Behcet's disease]] it can also result from environmental factors, such as from smoking tobacco products and exposure to air pollution.


In addition to acting as a [[semipermeable membrane]], the endothelium is responsible for maintaining [[vascular tone]] and regulating [[oxidative stress]] by releasing mediators, such as nitric oxide, [[prostacyclin]] and [[endothelin]], and by controlling local [[angiotensin]]-II activity.<ref>{{Cite journal|last1=Sitia|first1=S.|last2=Tomasoni|first2=L.|last3=Atzeni|first3=F.|last4=Ambrosio|first4=G.|last5=Cordiano|first5=C.|last6=Catapano|first6=A.|last7=Tramontana|first7=S.|last8=Perticone|first8=F.|last9=Naccarato|first9=P.|title=From endothelial dysfunction to atherosclerosis|journal=Autoimmunity Reviews|volume=9|issue=12|pages=830–834|doi=10.1016/j.autrev.2010.07.016|pmid=20678595|year=2010}}</ref><ref>{{cite journal |vauthors=Flammer AJ, Anderson T, Celermajer DS, Creager MA, Deanfield J, Ganz P, Hamburg NM, Lüscher TF, Shechter M, Taddei S, Vita JA, Lerman A | date = Aug 2012 | title = The assessment of endothelial function: from research into clinical practice | journal = Circulation | volume = 126 | issue = 6| pages = 753–67 | doi=10.1161/circulationaha.112.093245| pmid = 22869857 | pmc = 3427943 }}</ref>
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==Atherosclerosis==
Endothelial dysfunction is thought to be a key event in the development of [[atherosclerosis]] and predates clinically obvious vascular pathology by many years. This is because endothelial dysfunction is associated with reduced anticoagulant properties as well as increased [[adhesion molecule]] expression, chemokine and other cytokine release, and [[reactive oxygen species]] production from the endothelium, all of which play important roles in the development of atherosclerosis.


Dysfunctional endothelium is characterized by [[vasoconstriction]], increased [[vascular permeability]], [[thrombosis]], and [[inflammation]]. This pathological state is often associated with elevated levels of [[biomarker]]s such as [[prothrombin time]], [[D-dimer]], [[von Willebrand factor]], [[fibrin degradation product]]s, [[C-reactive protein]] (CRP), [[ferritin]], [[Interleukin 6]] (IL-6), and plasma [[creatinine]]. The result of this endothelial dysregulation is a cascade of adverse effects, including vasoconstriction, [[Capillary leak syndrome|vascular leakage]], thrombosis, hyperinflammation, and a disrupted antiviral [[immune response]]. These changes contribute to the progression of vascular diseases.<ref name=":0">{{Cite journal |last1=Bernard |first1=Isabelle |last2=Limonta |first2=Daniel |last3=Mahal |first3=Lara K. |last4=Hobman |first4=Tom C. |date=January 2021 |title=Endothelium Infection and Dysregulation by SARS-CoV-2: Evidence and Caveats in COVID-19 |journal=Viruses |language=en |volume=13 |issue=1 |pages=29 |doi=10.3390/v13010029 |pmid=33375371 |pmc=7823949 |issn=1999-4915 |doi-access=free }}</ref>
In fact, endothelial dysfunction has been shown to be of prognostic significance in predicting vascular events including stroke and heart attacks. Because of this, endothelial function testing may have great potential prognostic value for the detection of cardiovascular disease, but currently the available tests are too difficult, expensive, and/or variable for routine clinical use.


In a healthy state, the endothelium exhibits [[vasodilation]], tightly controlled vascular permeability, and anti-thrombotic and anti-inflammatory properties. This balance ensures the smooth functioning of the vascular system.<ref name=":0" />
==NO bioavailability==
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 [[nitric oxide]] (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.


==Research==
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 [[angiogram|intracoronary catheterisation]].
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=== Atherosclerosis ===
[[File:Atherosclerosis timeline - endothelial dysfunction.svg|thumb|Stages of endothelial dysfunction in atherosclerosis of arteries]]
Endothelial dysfunction may be involved in the development of [[atherosclerosis]]<ref name="jh">{{cite journal|pmid=29664811|year=2018|last1=Maruhashi|first1=T|title=Assessment of endothelium-independent vasodilation: From methodology to clinical perspectives|journal=Journal of Hypertension|volume=36|issue=7|pages=1460–1467|last2=Kihara|first2=Y|last3=Higashi|first3=Y|doi=10.1097/HJH.0000000000001750|s2cid=4948849}}</ref><ref name="pmid24222847">{{cite journal | vauthors = Eren E, Yilmaz N, Aydin O | title = Functionally defective high-density lipoprotein and paraoxonase: a couple for endothelial dysfunction in atherosclerosis | journal = Cholesterol | volume = 2013 | pages = 792090 | date = 2013 | pmid = 24222847 | pmc = 3814057 | doi = 10.1155/2013/792090 | doi-access = free }}</ref><ref name="botts-2021">{{cite journal | vauthors = Botts SR, Fish JE, Howe KL | title = Dysfunctional Vascular Endothelium as a Driver of Atherosclerosis: Emerging Insights Into Pathogenesis and Treatment | journal = Frontiers in Pharmacology | volume = 12 | pages = 787541 | date = December 2021 | pmid = 35002720 | pmc = 8727904 | doi = 10.3389/fphar.2021.787541 | doi-access = free }}</ref> and may predate vascular pathology.<ref name=jh/><ref name="pmid18382884">{{cite journal | vauthors = Münzel T, Sinning C, Post F, Warnholtz A, Schulz E | title = Pathophysiology, diagnosis and prognostic implications of endothelial dysfunction | journal = Annals of Medicine | volume = 40 | issue = 3 | pages = 180–96 | date = 2008 | pmid = 18382884 | doi = 10.1080/07853890701854702 | s2cid = 18542183 | doi-access = free }}</ref> Endothelial dysfunction may also lead to increased adherence of [[monocyte]]s and [[macrophage]]s, as well as promoting infiltration of [[low-density lipoprotein]] (LDL) in the vessel wall.<ref>{{Cite journal |last=Poredos |first=P. |date=2001 |title=Endothelial dysfunction in the pathogenesis of atherosclerosis |url=https://pubmed.ncbi.nlm.nih.gov/11697708/ |journal=Clinical and Applied Thrombosis/Hemostasis|volume=7 |issue=4 |pages=276–280 |doi=10.1177/107602960100700404 |issn=1076-0296 |pmid=11697708|s2cid=71334997 }}</ref> [[Low-density lipoprotein#Oxidized LDL|Oxidized LDL]] is a hallmark feature of atherosclerosis,<ref name="pmid25804383" /> by promoting the formation of [[foam cell]]s, [[monocyte]] [[chemotaxis]], and platelet activation, leading to [[Atheroma|atheromatous plaque]] instability and ultimately to rupture.<ref name="pmid35722128">{{cite journal | vauthors = Jiang M, Zhou Y, Ge J | title=Mechanisms of Oxidized LDL-Mediated Endothelial Dysfunction and Its Consequences for the Development of Atherosclerosis | journal= [[Frontiers in Cardiovascular Medicine]] | volume=9 | pages=925923 | year=2022 | doi= 10.3389/fcvm.2022.925923 | pmc=9199460 | pmid=35722128 | doi-access=free }}</ref> [[Dyslipidemia]] and [[hypertension]] are well known to contribute to endothelial dysfunction,<ref>{{Cite journal |last1=Le Master |first1=Elizabeth |last2=Levitan |first2=Irena |date=2019-01-22 |title=Endothelial stiffening in dyslipidemia |journal=Aging |volume=11 |issue=2 |pages=299–300 |doi=10.18632/aging.101778 |issn=1945-4589 |pmc=6366977 |pmid=30674709}}</ref><ref>{{Cite book |last1=Konukoglu |first1=Dildar |last2=Uzun |first2=Hafize |chapter=Endothelial Dysfunction and Hypertension |date=2017 |title=Hypertension: From basic research to clinical practice |url=https://pubmed.ncbi.nlm.nih.gov/28035582/ |series=Advances in Experimental Medicine and Biology |volume=956 |pages=511–540 |doi=10.1007/5584_2016_90 |issn=0065-2598 |pmid=28035582|isbn=978-3-319-44250-1 }}</ref> and lowering blood pressure and LDL has been shown to improve endothelial function, particularly when lowered with [[ACE inhibitor]]s, [[calcium channel blocker]]s, and [[statin]]s.<ref name="pubmed.ncbi.nlm.nih.gov">{{Cite journal |last1=Ghiadoni |first1=Lorenzo |last2=Taddei |first2=Stefano |last3=Virdis |first3=Agostino |date=2012 |title=Hypertension and endothelial dysfunction: therapeutic approach |url=https://pubmed.ncbi.nlm.nih.gov/22112351/#:~:text=A%20large%20body%20of%20evidence%20indicates%20that%20patients,changes%20and%20can%20also%20contribute%20to%20cardiovascular%20events. |journal=Current Vascular Pharmacology |volume=10 |issue=1 |pages=42–60 |doi=10.2174/157016112798829823 |issn=1875-6212 |pmid=22112351}}</ref> Steadily laminar flow with high shear stress in blood vessels protects against atherosclerosis, whereas disturbed flow promotes atherosclerosis.<ref name="pmid31354915" />


===Nitric oxide===
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]]. 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.
Nitric oxide (NO) suppresses platelet aggregation, inflammation, oxidative stress, vascular smooth muscle cell migration and proliferation, and leukocyte adhesion.<ref name="pmid24222847" /> A feature of endothelial dysfunction is the inability of [[arteries]] and [[arterioles]] to dilate fully in response to an appropriate stimulus, such as [[exogenous]] [[nitroglycerine]],<ref name=jh/> that stimulates release of [[Vasodilation|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 or inactivation of NO by reactive [[oxygen]] species.<ref name="pmid25804383">{{cite journal | vauthors = Gradinaru D, Borsa C, Prada GI | title=Oxidized LDL and NO synthesis--Biomarkers of endothelial dysfunction and ageing | journal= Mechanisms of Ageing and Development | volume=151 | pages=101–113 | year=2015 | doi= 10.1016/j.mad.2015.03.003 | pmid=25804383| doi-access=free }}</ref><ref name="pmid29596860">{{cite journal | vauthors = Yuyun MF, Ng LL, Ng GA | title=Endothelial dysfunction, endothelial nitric oxide bioavailability, tetrahydrobiopterin, and 5-methyltetrahydrofolate in cardiovascular disease. Where are we with therapy? | journal= Microvascular Research | volume=119 | pages=7–12 | year=2018 | doi= 10.1016/j.mvr.2018.03.012 | pmid=29596860}}</ref> As a co-factor for [[nitric oxide synthase]], [[tetrahydrobiopterin]] (BH4) supplementation has shown beneficial results for the treatment of endothelial dysfunction in animal experiments and clinical trials, although the tendency of BH4 to become oxidized to BH2 remains a problem.<ref name="pmid29596860" />


=== Testing and diagnosis ===
Because NO has anti-inflammatory and anti-proliferative effects and therefore helps inhibit atherosclerosis, it is easy to see how endothelial dysfunction may contribute to future adverse cardiovascular events. Unfortunately the variability in such tests (e.g. due to time of day, food, menstrual cycle, temperature, etc.) means that no technique has yet been identified that would allow endothelial testing to attain routine clinical significance, although there are some tests under clinical evaluation such as measuring of arterial stiffness.


In the [[coronary circulation]], [[angiography]] of [[coronary artery]] responses to vasoactive agents may be used to test for endothelial function, and venous occlusion [[plethysmography]] and [[ultrasonography]] are used to assess endothelial function of peripheral vessels in humans.<ref name=jh/>
==Testing==
The gold standard for measuring endothelial function is angiography with acetylcholine injection<ref>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</ref> , however due to the invasive and complex nature of the procedure it has never been used outside research<ref>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.</ref>.
A noninvasive method to measure endothelial dysfunction is ultrasound Flow Mediated Vasodilation (FMD).
There are serious flaws in measurements of endothelial function with FMD which involve the percentage change in diameter as the selected statistic. There is a negative correlation between percent flow mediated dilation and baseline artery size, but this has only recently been recognised as a fundamental scaling problem, showing that peak diameter does not change as a constant proportion of baseline diameter. This dependence of percent FMD on baseline diameter can lead to biased estimates of endothelial function. For research on FMD an ANCOVA approach to adjusting FMD for variation in baseline diameter is more appropriate. A major challenge of FMD is also the variability across centers and the requirement of highly qualified technicians to perform the procedure<ref>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 </ref>.
<br>An FDA approved non-invasive device for measuring Endothelial function, EndoPAT,<ref> 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. </ref><ref>Axtell AL, Gomari FA, Cooke JP. Assessing endothelial vasodilator function
with the Endo-PAT 2000. J Vis Exp. 2010 Oct 15;(44).</ref> has been tested in several clinical trials in multiple centers. It works through the method of Peripheral Arterial Tonometry (PAT). Results from clinical trials have shown that Endopat is useful for risk evaluation, stratification and prognosis of getting major cardiovascualar events (MACE).<ref>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.</ref> <ref>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.</ref> <ref>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.</ref><ref>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</ref> <ref>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. </ref><ref>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.</ref><ref>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.</ref><ref>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</ref>


A [[Minimally invasive procedures|non-invasive]] method to measure endothelial dysfunction is % [[Flow-mediated dilation|Flow-Mediated Dilation]] (FMD) as measured by Brachial Artery Ultrasound Imaging (BAUI).<ref>{{cite journal|last=Peretz|first=Alon|author2=Daniel F Leotta |author3=Jeffrey H Sullivan |author4=Carol A Trenga |author5=Fiona N Sands |author6=Mary R Aulet |title=Flow mediated dilation of the brachial artery: an investigation of methods requiring further standardization|journal=BMC Cardiovascular Disorders|year=2007|volume=7|issue=11|pages=11|doi=10.1186/1471-2261-7-11|pmid=17376239|pmc=1847451 |doi-access=free }}</ref> Current measurements of endothelial function via FMD vary due to technical and physiological factors. Furthermore, a [[Negative relationship|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.<ref>{{cite journal |vauthors=Thijssen DH, Black MA, Pyke KE, Padilla J, Atkinson G, Harris RA, Parker B, Widlansky ME, Tschakovsky ME, Green DJ | date = Jan 2011 | title = Assessment of flow-mediated dilation in humans: a methodological and physiological guideline | journal = Am J Physiol Heart Circ Physiol | volume = 300 | issue = 1| pages = H2–12 | doi=10.1152/ajpheart.00471.2010| pmid = 20952670 | pmc = 3023245 }}</ref>
==Prevention and treatment==
Endothelial function can be improved significantly by exercise and improved diet. A study published in 2005 has determined that a positive relationship exists between the consumption of [[trans fat]] (commonly found in [[hydrogenated]] products such as [[margarine]]) and the development of endothelial dysfunction.<ref>Lopez-Garcia E, Schulze MB, Meigs JB, [[JoAnn E. Manson|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.</ref> Other factors have been identified as improving endothelial function and include cessation of smoking, loss of weight and treatment of [[hypertension]] and [[hypercholesterolemia]] amongst other things. Some studies have found [[antioxidants]], [[potassium]]<ref>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)</ref>
and [[arginine]] supplementation to restore impaired endothelial function.
New third-generation β-blockers and 5-phosphodiesterase inhibitors may affect endothelial function. However to date it remains not possible to assess which set of patients are improving their endothelial function. Furthermore, the HMGCoA-reductase inhibitors currently used to reduce cholesterol levels have major pleiotropic anti-inflammatory and anti-hypertensive effects. The preservation or recovery of endothelial function in hypertensive patients is crucial to inhibit the development of atherosclerosis and the onset of cardiovascular events. This review focuses on the ancillary effects of hypertensive drugs and HMGCoA-reductase inhibitors that go beyond lowering blood pressure and cholesterol levels.<ref>Tomasoni L, Sitia S, Borghi C, Cicero AF, Ceconi C, [http://www1.imperial.ac.uk/medicine/people/f.cecaro 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</ref>


[[von Willebrand factor]] is a marker of endothelial dysfunction, and is consistently elevated in [[atrial fibrillation]].<ref name="pmid31631989">{{cite journal | vauthors = Khan AA, Thomas GN, Lip G, Shantsila A | title=Endothelial function in patients with atrial fibrillation | journal= [[Annals of Medicine]] | volume=52 | issue=1–2 | pages=1–11 | year=2020 | doi= 10.1080/07853890.2019.1711158 | pmc=7877921 | pmid=31903788 }}</ref>
==Epidemiology==
Endothelial dysfunction has been observed in a 2001 study of women where it was found that this disorder is present 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.<ref>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</ref>


A non-invasive, [[Food and Drug Administration|FDA]]-approved device for measuring endothelial function that works by measuring [[Hyperaemia#Reactive hyperaemia|Reactive Hyperemia]] Index (RHI) is [[Itamar Medical]]'s EndoPAT.<ref>{{cite journal |vauthors=Kuvin JT, Mammen A, Mooney P, Alsheikh-Ali AA, Karas RH | date = Feb 2007 | title = Assessment of peripheral vascular endothelial function in the ambulatory setting | journal = Vasc. Med. | volume = 12 | issue = 1| pages = 13–6 | doi=10.1177/1358863x06076227| pmid = 17451088 | doi-access = free }}</ref><ref name="pmid20972417">{{cite journal | vauthors = Axtell AL, Gomari FA, Cooke JP | title = Assessing endothelial vasodilator function with the Endo-PAT 2000 | journal = Journal of Visualized Experiments | issue = 44 | date = October 2010 | pmid = 20972417 | pmc = 3143035 | doi = 10.3791/2167 }}</ref> It has shown an 80% sensitivity and 86% specificity to diagnose [[coronary artery disease]] when compared against the gold standard, acetylcholine angiogram.<ref>{{cite journal |vauthors=Bonetti PO, Pumper GM, Higano ST, ((Holmes DR Jr)), Kuvin JT, Lerman A | date = Dec 2004 | title = Noninvasive identification of patients with early coronary atherosclerosis by assessment of digital reactive hyperemia | journal = J Am Coll Cardiol | volume = 44 | issue = 11| pages = 2137–41 | doi=10.1016/j.jacc.2004.08.062| pmid = 15582310 | doi-access = free }}</ref> This results suggests that this peripheral test reflects the physiology of the [[Coronary circulation|coronary]] endothelium.
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==See also==

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* [[Endothelium-derived relaxing factor]]
Since NO maintains low tone and high compliance of the small arteries at rest,<ref>{{cite journal |vauthors=Gilani M, Kaiser DR, Bratteli CW, Alinder C, Rajala Bank AJ, Cohn JN | year = 2007 | title = Role of nitric oxide deficiency and its detection as a risk factor in pre-hypertension | journal = JASH | volume = 1 | issue = 1| pages = 45–56 | doi=10.1016/j.jash.2006.11.002| pmid = 20409832 }}</ref> a reduction of age-dependent small artery compliance is a marker for endothelial dysfunction that is associated with both functional and structural changes in the microcirculation.<ref>{{cite journal |vauthors=Duprez DA, Jacobs DR, Lutsey PL, Bluemke FA, Brumback LC, Polak JF, Peralta CA, Greenland P, Kronmal RA | year = 2011 | title = Association of small artery elasticity with incident cardiovascular disease in older adults: the multiethnic study of atherosclerosis | journal = Am J Epidemiol | volume = 174 | issue = 5| pages = 528–36 | doi=10.1093/aje/kwr120| pmid = 21709134 | pmc = 3202150 }}</ref> Small artery compliance or stiffness can be assessed simply and at rest and can be distinguished from large artery stiffness by use of pulsewave analysis.<ref>{{cite journal |vauthors=Cohn JN, Duprez DA, Finkelstein SM | year = 2009 | title = Comprehensive noninvasive arterial vascular evaluation | journal = Future Cardiology | volume = 5 | issue = 6| pages = 573–9 | doi=10.2217/fca.09.44| pmid = 19886784 }}</ref>

=== Endothelial dysfunction and stents ===
[[Stent]] implantation has been correlated with impaired endothelial function in several studies.<ref name="jte">{{cite journal|pmc=5624345|year=2017|last1=Bedair|first1=T. M|title=Recent advances to accelerate re-endothelialization for vascular stents|journal=Journal of Tissue Engineering|volume=8|pages=2041731417731546|last2=Elnaggar|first2=M. A|last3=Joung|first3=Y. K|last4=Han|first4=D. K|doi=10.1177/2041731417731546|pmid=28989698}}</ref> [[Sirolimus]] eluting stents were previously used because they showed low rates of in-stent [[restenosis]], but further investigation showed that they often impair endothelial function in humans and worsen conditions.<ref name=jte/> One drug used to inhibit restenosis is [[iopromide]]-[[paclitaxel]].<ref>{{Cite journal|last1=Unverdorben|first1=Martin|last2=Vallbracht|first2=Christian|last3=Cremers|first3=Bodo|last4=Heuer|first4=Hubertus|last5=Hengstenberg|first5=Christian|last6=Maikowski|first6=Christian|last7=Werner|first7=Gerald S.|last8=Antoni|first8=Diethmar|last9=Kleber|first9=Franz X.|date=2009-06-16|title=Paclitaxel-coated balloon catheter versus paclitaxel-coated stent for the treatment of coronary in-stent restenosis|journal=Circulation|language=en|volume=119|issue=23|pages=2986–2994|doi=10.1161/circulationaha.108.839282|issn=0009-7322|pmid=19487593|doi-access=free}}</ref>

=== COVID-19 complication in the lungs ===

COVID-19 can present with an acute lung injury manifestation that arises from endothelial dysfunction.<ref>{{cite journal |last1=Xu |first1=Suo-wen |last2=Ilyas |first2=Iqra |last3=Weng |first3=Jian-ping |title=Endothelial dysfunction in COVID-19: an overview of evidence, biomarkers, mechanisms and potential therapies |journal=Acta Pharmacologica Sinica |date=April 2023 |volume=44 |issue=4 |pages=695–709 |doi=10.1038/s41401-022-00998-0|pmid=36253560 |pmc=9574180 }}</ref>

=== Risk reduction ===
Treatment of [[hypertension]] and [[hypercholesterolemia]] may improve endothelial function in people taking [[statins]] (HMGCoA-reductase inhibitor), and [[renin]] [[angiotensin]] system inhibitors, such as [[ACE inhibitors]] and [[angiotensin II receptor antagonists]].<ref name="pmid17583170">{{cite journal | vauthors = Ruilope LM, Redón J, Schmieder R | title = Cardiovascular risk reduction by reversing endothelial dysfunction: ARBs, ACE inhibitors, or both? Expectations from the ONTARGET Trial Programme | journal = Vascular Health and Risk Management | volume = 3 | issue = 1 | pages = 1–9 | date = 2007 | pmid = 17583170 | pmc = 1994043 }}</ref><ref>{{cite journal |vauthors=Briasoulis A, Tousoulis D, Androulakis ES, Papageorgiou N, Latsios G, Stefanadis C | date = Apr 2012 | title = Endothelial dysfunction and atherosclerosis: focus on novel therapeutic approaches | journal = Recent Pat Cardiovasc Drug Discov | volume = 7 | issue = 1| pages = 21–32 | doi=10.2174/157489012799362386| pmid = 22280336 }}</ref> Calcium channel blockers and selective beta 1 antagonists may also improve endothelial dysfunction.<ref name="pubmed.ncbi.nlm.nih.gov"/> Life style modifications such as smoking cessation have also been shown to improve endothelial function and lower the risk of major cardiovascular events.<ref>{{Cite journal |last1=Messner |first1=Barbara |last2=Bernhard |first2=David |date=2014 |title=Smoking and cardiovascular disease: mechanisms of endothelial dysfunction and early atherogenesis |journal=Arteriosclerosis, Thrombosis, and Vascular Biology |volume=34 |issue=3 |pages=509–515 |doi=10.1161/ATVBAHA.113.300156 |issn=1524-4636 |pmid=24554606|doi-access=free }}</ref>

⚫
== See also ==
* [[Atherosclerosis]]
* [[Endothelial activation]]
* [[Endothelial activation]]
* [[Nitric oxide]]
* endothelial [[nitric oxide synthase]]
* [[Prostacyclin]]
⚫
* [[Endothelium-derived relaxing factor]]
* [[Endothelin]]
* [[Integrin]] network
* Endothelial [[shear stress]]


==References==
== References ==
{{reflist|colwidth=30em}}
<references/>


{{Authority control}}
==External links==
*[http://www.cardiovance.com/page/19kyl/Heart_Disease_In_Women.html Information on heart disease in women]


[[Category:Vascular diseases]]
[[Category:Vascular diseases]]

[[it:Disfunzione endoteliale]]

Latest revision as of 17:52, 11 October 2024

Comparison of healthy vs. dysfunctional vascular endothelium

In vascular diseases, endothelial dysfunction is a systemic pathological state of the endothelium. The main cause of endothelial dysfunction is impaired bioavailability of nitric oxide.[1]

In addition to acting as a semipermeable membrane, the endothelium is responsible for maintaining vascular tone and regulating oxidative stress by releasing mediators, such as nitric oxide, prostacyclin and endothelin, and by controlling local angiotensin-II activity.[2][3]

Dysfunctional endothelium is characterized by vasoconstriction, increased vascular permeability, thrombosis, and inflammation. This pathological state is often associated with elevated levels of biomarkers such as prothrombin time, D-dimer, von Willebrand factor, fibrin degradation products, C-reactive protein (CRP), ferritin, Interleukin 6 (IL-6), and plasma creatinine. The result of this endothelial dysregulation is a cascade of adverse effects, including vasoconstriction, vascular leakage, thrombosis, hyperinflammation, and a disrupted antiviral immune response. These changes contribute to the progression of vascular diseases.[4]

In a healthy state, the endothelium exhibits vasodilation, tightly controlled vascular permeability, and anti-thrombotic and anti-inflammatory properties. This balance ensures the smooth functioning of the vascular system.[4]

Research

[edit]

Atherosclerosis

[edit]
Stages of endothelial dysfunction in atherosclerosis of arteries

Endothelial dysfunction may be involved in the development of atherosclerosis[5][6][7] and may predate vascular pathology.[5][8] Endothelial dysfunction may also lead to increased adherence of monocytes and macrophages, as well as promoting infiltration of low-density lipoprotein (LDL) in the vessel wall.[9] Oxidized LDL is a hallmark feature of atherosclerosis,[10] by promoting the formation of foam cells, monocyte chemotaxis, and platelet activation, leading to atheromatous plaque instability and ultimately to rupture.[11] Dyslipidemia and hypertension are well known to contribute to endothelial dysfunction,[12][13] and lowering blood pressure and LDL has been shown to improve endothelial function, particularly when lowered with ACE inhibitors, calcium channel blockers, and statins.[14] Steadily laminar flow with high shear stress in blood vessels protects against atherosclerosis, whereas disturbed flow promotes atherosclerosis.[1]

Nitric oxide

[edit]

Nitric oxide (NO) suppresses platelet aggregation, inflammation, oxidative stress, vascular smooth muscle cell migration and proliferation, and leukocyte adhesion.[6] A feature of endothelial dysfunction is the inability of arteries and arterioles to dilate fully in response to an appropriate stimulus, such as exogenous nitroglycerine,[5] 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 or inactivation of NO by reactive oxygen species.[10][15] As a co-factor for nitric oxide synthase, tetrahydrobiopterin (BH4) supplementation has shown beneficial results for the treatment of endothelial dysfunction in animal experiments and clinical trials, although the tendency of BH4 to become oxidized to BH2 remains a problem.[15]

Testing and diagnosis

[edit]

In the coronary circulation, angiography of coronary artery responses to vasoactive agents may be used to test for endothelial function, and venous occlusion plethysmography and ultrasonography are used to assess endothelial function of peripheral vessels in humans.[5]

A non-invasive method to measure endothelial dysfunction is % Flow-Mediated Dilation (FMD) as measured by Brachial Artery Ultrasound Imaging (BAUI).[16] Current measurements of endothelial function via FMD vary due to technical and physiological factors. Furthermore, 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.[17]

von Willebrand factor is a marker of endothelial dysfunction, and is consistently elevated in atrial fibrillation.[18]

A non-invasive, FDA-approved device for measuring endothelial function that works by measuring Reactive Hyperemia Index (RHI) is Itamar Medical's EndoPAT.[19][20] It has shown an 80% sensitivity and 86% specificity to diagnose coronary artery disease when compared against the gold standard, acetylcholine angiogram.[21] This results suggests that this peripheral test reflects the physiology of the coronary endothelium.

Since NO maintains low tone and high compliance of the small arteries at rest,[22] a reduction of age-dependent small artery compliance is a marker for endothelial dysfunction that is associated with both functional and structural changes in the microcirculation.[23] Small artery compliance or stiffness can be assessed simply and at rest and can be distinguished from large artery stiffness by use of pulsewave analysis.[24]

Endothelial dysfunction and stents

[edit]

Stent implantation has been correlated with impaired endothelial function in several studies.[25] Sirolimus eluting stents were previously used because they showed low rates of in-stent restenosis, but further investigation showed that they often impair endothelial function in humans and worsen conditions.[25] One drug used to inhibit restenosis is iopromide-paclitaxel.[26]

COVID-19 complication in the lungs

[edit]

COVID-19 can present with an acute lung injury manifestation that arises from endothelial dysfunction.[27]

Risk reduction

[edit]

Treatment of hypertension and hypercholesterolemia may improve endothelial function in people taking statins (HMGCoA-reductase inhibitor), and renin angiotensin system inhibitors, such as ACE inhibitors and angiotensin II receptor antagonists.[28][29] Calcium channel blockers and selective beta 1 antagonists may also improve endothelial dysfunction.[14] Life style modifications such as smoking cessation have also been shown to improve endothelial function and lower the risk of major cardiovascular events.[30]

See also

[edit]

References

[edit]
  1. ^ a b Marchio P, Guerra-Ojeda S, Mauricio MD (2019). "Targeting Early Atherosclerosis: A Focus on Oxidative Stress and Inflammation". Oxidative Medicine and Cellular Longevity. 2019: 8563845. doi:10.1155/2019/8563845. PMC 6636482. PMID 31354915.
  2. ^ Sitia, S.; Tomasoni, L.; Atzeni, F.; Ambrosio, G.; Cordiano, C.; Catapano, A.; Tramontana, S.; Perticone, F.; Naccarato, P. (2010). "From endothelial dysfunction to atherosclerosis". Autoimmunity Reviews. 9 (12): 830–834. doi:10.1016/j.autrev.2010.07.016. PMID 20678595.
  3. ^ Flammer AJ, Anderson T, Celermajer DS, Creager MA, Deanfield J, Ganz P, Hamburg NM, Lüscher TF, Shechter M, Taddei S, Vita JA, Lerman A (Aug 2012). "The assessment of endothelial function: from research into clinical practice". Circulation. 126 (6): 753–67. doi:10.1161/circulationaha.112.093245. PMC 3427943. PMID 22869857.
  4. ^ a b Bernard, Isabelle; Limonta, Daniel; Mahal, Lara K.; Hobman, Tom C. (January 2021). "Endothelium Infection and Dysregulation by SARS-CoV-2: Evidence and Caveats in COVID-19". Viruses. 13 (1): 29. doi:10.3390/v13010029. ISSN 1999-4915. PMC 7823949. PMID 33375371.
  5. ^ a b c d Maruhashi, T; Kihara, Y; Higashi, Y (2018). "Assessment of endothelium-independent vasodilation: From methodology to clinical perspectives". Journal of Hypertension. 36 (7): 1460–1467. doi:10.1097/HJH.0000000000001750. PMID 29664811. S2CID 4948849.
  6. ^ a b Eren E, Yilmaz N, Aydin O (2013). "Functionally defective high-density lipoprotein and paraoxonase: a couple for endothelial dysfunction in atherosclerosis". Cholesterol. 2013: 792090. doi:10.1155/2013/792090. PMC 3814057. PMID 24222847.
  7. ^ Botts SR, Fish JE, Howe KL (December 2021). "Dysfunctional Vascular Endothelium as a Driver of Atherosclerosis: Emerging Insights Into Pathogenesis and Treatment". Frontiers in Pharmacology. 12: 787541. doi:10.3389/fphar.2021.787541. PMC 8727904. PMID 35002720.
  8. ^ Münzel T, Sinning C, Post F, Warnholtz A, Schulz E (2008). "Pathophysiology, diagnosis and prognostic implications of endothelial dysfunction". Annals of Medicine. 40 (3): 180–96. doi:10.1080/07853890701854702. PMID 18382884. S2CID 18542183.
  9. ^ Poredos, P. (2001). "Endothelial dysfunction in the pathogenesis of atherosclerosis". Clinical and Applied Thrombosis/Hemostasis. 7 (4): 276–280. doi:10.1177/107602960100700404. ISSN 1076-0296. PMID 11697708. S2CID 71334997.
  10. ^ a b Gradinaru D, Borsa C, Prada GI (2015). "Oxidized LDL and NO synthesis--Biomarkers of endothelial dysfunction and ageing". Mechanisms of Ageing and Development. 151: 101–113. doi:10.1016/j.mad.2015.03.003. PMID 25804383.
  11. ^ Jiang M, Zhou Y, Ge J (2022). "Mechanisms of Oxidized LDL-Mediated Endothelial Dysfunction and Its Consequences for the Development of Atherosclerosis". Frontiers in Cardiovascular Medicine. 9: 925923. doi:10.3389/fcvm.2022.925923. PMC 9199460. PMID 35722128.
  12. ^ Le Master, Elizabeth; Levitan, Irena (2019-01-22). "Endothelial stiffening in dyslipidemia". Aging. 11 (2): 299–300. doi:10.18632/aging.101778. ISSN 1945-4589. PMC 6366977. PMID 30674709.
  13. ^ Konukoglu, Dildar; Uzun, Hafize (2017). "Endothelial Dysfunction and Hypertension". Hypertension: From basic research to clinical practice. Advances in Experimental Medicine and Biology. Vol. 956. pp. 511–540. doi:10.1007/5584_2016_90. ISBN 978-3-319-44250-1. ISSN 0065-2598. PMID 28035582.
  14. ^ a b Ghiadoni, Lorenzo; Taddei, Stefano; Virdis, Agostino (2012). "Hypertension and endothelial dysfunction: therapeutic approach". Current Vascular Pharmacology. 10 (1): 42–60. doi:10.2174/157016112798829823. ISSN 1875-6212. PMID 22112351.
  15. ^ a b Yuyun MF, Ng LL, Ng GA (2018). "Endothelial dysfunction, endothelial nitric oxide bioavailability, tetrahydrobiopterin, and 5-methyltetrahydrofolate in cardiovascular disease. Where are we with therapy?". Microvascular Research. 119: 7–12. doi:10.1016/j.mvr.2018.03.012. PMID 29596860.
  16. ^ 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): 11. doi:10.1186/1471-2261-7-11. PMC 1847451. PMID 17376239.
  17. ^ Thijssen DH, Black MA, Pyke KE, Padilla J, Atkinson G, Harris RA, Parker B, Widlansky ME, Tschakovsky ME, Green DJ (Jan 2011). "Assessment of flow-mediated dilation in humans: a methodological and physiological guideline". Am J Physiol Heart Circ Physiol. 300 (1): H2–12. doi:10.1152/ajpheart.00471.2010. PMC 3023245. PMID 20952670.
  18. ^ Khan AA, Thomas GN, Lip G, Shantsila A (2020). "Endothelial function in patients with atrial fibrillation". Annals of Medicine. 52 (1–2): 1–11. doi:10.1080/07853890.2019.1711158. PMC 7877921. PMID 31903788.
  19. ^ Kuvin JT, Mammen A, Mooney P, Alsheikh-Ali AA, Karas RH (Feb 2007). "Assessment of peripheral vascular endothelial function in the ambulatory setting". Vasc. Med. 12 (1): 13–6. doi:10.1177/1358863x06076227. PMID 17451088.
  20. ^ Axtell AL, Gomari FA, Cooke JP (October 2010). "Assessing endothelial vasodilator function with the Endo-PAT 2000". Journal of Visualized Experiments (44). doi:10.3791/2167. PMC 3143035. PMID 20972417.
  21. ^ Bonetti PO, Pumper GM, Higano ST, Holmes DR Jr, Kuvin JT, Lerman A (Dec 2004). "Noninvasive identification of patients with early coronary atherosclerosis by assessment of digital reactive hyperemia". J Am Coll Cardiol. 44 (11): 2137–41. doi:10.1016/j.jacc.2004.08.062. PMID 15582310.
  22. ^ Gilani M, Kaiser DR, Bratteli CW, Alinder C, Rajala Bank AJ, Cohn JN (2007). "Role of nitric oxide deficiency and its detection as a risk factor in pre-hypertension". JASH. 1 (1): 45–56. doi:10.1016/j.jash.2006.11.002. PMID 20409832.
  23. ^ Duprez DA, Jacobs DR, Lutsey PL, Bluemke FA, Brumback LC, Polak JF, Peralta CA, Greenland P, Kronmal RA (2011). "Association of small artery elasticity with incident cardiovascular disease in older adults: the multiethnic study of atherosclerosis". Am J Epidemiol. 174 (5): 528–36. doi:10.1093/aje/kwr120. PMC 3202150. PMID 21709134.
  24. ^ Cohn JN, Duprez DA, Finkelstein SM (2009). "Comprehensive noninvasive arterial vascular evaluation". Future Cardiology. 5 (6): 573–9. doi:10.2217/fca.09.44. PMID 19886784.
  25. ^ a b Bedair, T. M; Elnaggar, M. A; Joung, Y. K; Han, D. K (2017). "Recent advances to accelerate re-endothelialization for vascular stents". Journal of Tissue Engineering. 8: 2041731417731546. doi:10.1177/2041731417731546. PMC 5624345. PMID 28989698.
  26. ^ Unverdorben, Martin; Vallbracht, Christian; Cremers, Bodo; Heuer, Hubertus; Hengstenberg, Christian; Maikowski, Christian; Werner, Gerald S.; Antoni, Diethmar; Kleber, Franz X. (2009-06-16). "Paclitaxel-coated balloon catheter versus paclitaxel-coated stent for the treatment of coronary in-stent restenosis". Circulation. 119 (23): 2986–2994. doi:10.1161/circulationaha.108.839282. ISSN 0009-7322. PMID 19487593.
  27. ^ Xu, Suo-wen; Ilyas, Iqra; Weng, Jian-ping (April 2023). "Endothelial dysfunction in COVID-19: an overview of evidence, biomarkers, mechanisms and potential therapies". Acta Pharmacologica Sinica. 44 (4): 695–709. doi:10.1038/s41401-022-00998-0. PMC 9574180. PMID 36253560.
  28. ^ Ruilope LM, Redón J, Schmieder R (2007). "Cardiovascular risk reduction by reversing endothelial dysfunction: ARBs, ACE inhibitors, or both? Expectations from the ONTARGET Trial Programme". Vascular Health and Risk Management. 3 (1): 1–9. PMC 1994043. PMID 17583170.
  29. ^ Briasoulis A, Tousoulis D, Androulakis ES, Papageorgiou N, Latsios G, Stefanadis C (Apr 2012). "Endothelial dysfunction and atherosclerosis: focus on novel therapeutic approaches". Recent Pat Cardiovasc Drug Discov. 7 (1): 21–32. doi:10.2174/157489012799362386. PMID 22280336.
  30. ^ Messner, Barbara; Bernhard, David (2014). "Smoking and cardiovascular disease: mechanisms of endothelial dysfunction and early atherogenesis". Arteriosclerosis, Thrombosis, and Vascular Biology. 34 (3): 509–515. doi:10.1161/ATVBAHA.113.300156. ISSN 1524-4636. PMID 24554606.
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