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{{Short description|Impaired function of the inner lining of blood/lymph vessels}} | {{Short description|Impaired function of the inner lining of blood/lymph vessels}} | ||
{{more medical citations needed|date=April 2018}} | {{more medical citations needed|date=April 2018}} | ||
[[File:Viruses-13-00029-g001.webp|thumb|Comparison of healthy vs. dysfunctional vascular endothelium]] | [[File:Viruses-13-00029-g001.webp|thumb|Comparison of healthy vs. dysfunctional vascular endothelium]] | ||
In [[vascular disease]]s, '''endothelial dysfunction''' is | In [[vascular disease|blood vessel disease]]s, '''endothelial dysfunction''' is an unhealthy state of [[endothelium|the cells that line the blood vessels (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 | article-number=8563845 | year=2019 | doi= 10.1155/2019/8563845 | pmc=6636482 | pmid=31354915 | doi-access=free }}</ref> | ||
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> | 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> | ||
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 | Dysfunctional endothelium is characterized by [[vasoconstriction|constricted blood vessels]], increased [[vascular permeability|ability of chemicals to flow through blood vessel walls]], [[thrombosis|blood clots]], 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 harmful effects, including tightened blood vessels, [[Capillary leak syndrome|small blood vessel leakage]], blood clots, high levels of inflammation, and a disrupted [[immune response]] against [[virus]]es. These changes contribute to the progression of blood vessel (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 |page=29 |doi=10.3390/v13010029 |pmid=33375371 |pmc=7823949 |issn=1999-4915 |doi-access=free }}</ref> | ||
In a healthy state, the endothelium exhibits [[vasodilation]], tightly controlled | In a healthy state, the endothelium exhibits [[vasodilation|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.<ref name=":0" /> | ||
==Research== | ==Research== | ||
=== Atherosclerosis === | === Atherosclerosis === | ||
[[File:Atherosclerosis timeline - endothelial dysfunction.svg|thumb|Stages of endothelial dysfunction in atherosclerosis of arteries]] | [[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 | | 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 | article-number = 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 | article-number = 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 |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 | article-number=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 |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 |journal=Current Vascular Pharmacology |volume=10 |issue=1 |pages=42–60 |doi=10.2174/157016112798829823 |issn=1875-6212 |pmid=22112351}}</ref> Steady laminar flow with high shear stress in blood vessels protects against atherosclerosis, whereas disturbed flow promotes atherosclerosis.<ref name="pmid31354915" /> | ||
===Nitric oxide=== | ===Nitric oxide=== | ||
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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/> | 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| | 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|page=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 | [[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 | 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 result 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> | 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 === | === 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| | [[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|article-number=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 complication in the lungs === | ||
| Line 40: | Line 39: | ||
=== Risk reduction === | === 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"/> | Treatment of [[hypertension|high blood pressure]] and [[hypercholesterolemia|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]].<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"/> Lifestyle 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 == | == See also == | ||
| Line 46: | Line 45: | ||
* [[Endothelial activation]] | * [[Endothelial activation]] | ||
* [[Nitric oxide]] | * [[Nitric oxide]] | ||
* | * Endothelial [[nitric oxide synthase]] | ||
* [[Prostacyclin]] | * [[Prostacyclin]] | ||
* [[Endothelium-derived relaxing factor]] | * [[Endothelium-derived relaxing factor]] | ||
Latest revision as of 10:25, 30 September 2025
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In blood vessel diseases, endothelial dysfunction is an unhealthy state of the cells that line the blood vessels (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 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.[4]
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.[4]
Research
Atherosclerosis
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] Steady laminar flow with high shear stress in blood vessels protects against atherosclerosis, whereas disturbed flow promotes atherosclerosis.[1]
Nitric oxide
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
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 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,[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
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
COVID-19 can present with an acute lung injury manifestation that arises from endothelial dysfunction.[27]
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.[28][29] Calcium channel blockers and selective beta 1 antagonists may also improve endothelial dysfunction.[14] Lifestyle modifications such as smoking cessation have also been shown to improve endothelial function and lower the risk of major cardiovascular events.[30]
See also
- Atherosclerosis
- Endothelial activation
- Nitric oxide
- Endothelial nitric oxide synthase
- Prostacyclin
- Endothelium-derived relaxing factor
- Endothelin
- Integrin network
- Endothelial shear stress
References
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