endothelial dysfunction

{{Short description|Impaired function of the inner lining of blood/lymph vessels}}

In blood vessel diseases, endothelial dysfunction is an unhealthy state of the the cells that line the blood vessels (endothelium). The main cause of endothelial dysfunction is impaired bioavailability of nitric oxide.{{cite journal | vauthors = Marchio P, Guerra-Ojeda S, Mauricio MD | title=Targeting Early Atherosclerosis: A Focus on Oxidative Stress and Inflammation | journal= Oxidative Medicine and Cellular Longevity | volume=2019 | pages=8563845 | year=2019 | doi= 10.1155/2019/8563845 | pmc=6636482 | pmid=31354915 | doi-access=free }}

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.{{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}}{{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 }}

Dysfunctional endothelium is characterized by constricted blood vessels, increased ability of chemicals to flow through blood vessel walls, blood clots, 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 harmful effects, including tightened blood vessels, small blood vessel leakage, blood clots, high levels of inflammation, and a disrupted immune response against viruses. These changes contribute to the progression of blood vessel (vascular) diseases.{{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 }}

In a healthy state, the endothelium exhibits wider blood vessels, tightly-controlled blood vessel permeability, and anti-thrombotic and anti-inflammatory properties. This balance ensures the smooth functioning of the vascular system.

Research

= Atherosclerosis =

File:Atherosclerosis timeline - endothelial dysfunction.svg

Endothelial dysfunction may be involved in the development of atherosclerosis{{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}}{{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 }}{{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 }} and may predate vascular pathology.{{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 }} 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.{{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 }} Oxidized LDL is a hallmark feature of atherosclerosis, by promoting the formation of foam cells, monocyte chemotaxis, and platelet activation, leading to atheromatous plaque instability and ultimately to rupture.{{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 }} Dyslipidemia and hypertension are well known to contribute to endothelial dysfunction,{{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}}{{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 }} and lowering blood pressure and LDL has been shown to improve endothelial function, particularly when lowered with ACE inhibitors, calcium channel blockers, and statins.{{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}} Steady laminar flow with high shear stress in blood vessels protects against atherosclerosis, whereas disturbed flow promotes atherosclerosis.

=Nitric oxide=

Nitric oxide (NO) suppresses platelet aggregation, inflammation, oxidative stress, vascular smooth muscle cell migration and proliferation, and leukocyte adhesion. 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, 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.{{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 }}{{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}} 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.

= 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.

A non-invasive method to measure endothelial dysfunction is % Flow-Mediated Dilation (FMD) as measured by Brachial Artery Ultrasound Imaging (BAUI).{{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 }} 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.{{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 }}

von Willebrand factor is a marker of endothelial dysfunction and is consistently elevated in atrial fibrillation.{{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 }}

A non-invasive, FDA-approved device for measuring endothelial function that works by measuring Reactive Hyperemia Index (RHI) is Itamar Medical's EndoPAT.{{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 }}{{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 }} It has shown an 80% sensitivity and 86% specificity to diagnose coronary artery disease when compared against the gold standard, acetylcholine angiogram.{{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 }} This result 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,{{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 }} 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.{{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 }} 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.{{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 }}

= Endothelial dysfunction and stents =

Stent implantation has been correlated with impaired endothelial function in several studies.{{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}} 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. One drug used to inhibit restenosis is iopromide-paclitaxel.{{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}}

= COVID-19 complication in the lungs =

COVID-19 can present with an acute lung injury manifestation that arises from endothelial dysfunction.{{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 }}

= Risk reduction =

Treatment of high blood pressure and high levels of cholesterol in the blood 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.{{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 }}{{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 }} Calcium channel blockers and selective beta 1 antagonists may also improve endothelial dysfunction. Lifestyle modifications such as smoking cessation have also been shown to improve endothelial function and lower the risk of major cardiovascular events.{{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 }}

References

Category:Vascular diseases