Editing Endothelial dysfunction (section)

==Research==
=== 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===
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 ===

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/>

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>

[[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> 

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.

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>