Endothelial dysfunction

Short description: Impaired function of the inner lining of blood/lymph vessels

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Comparison of healthy vs. dysfunctional vascular endothelium

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]

## Contents

* 1 Research
* 1.1 Atherosclerosis
* 1.2 Nitric oxide
* 1.3 Testing and diagnosis
* 1.4 Endothelial dysfunction and stents
* 1.5 COVID-19 complication in the lungs
* 1.6 Risk reduction
* 2 See also
* 3 References

## Research

### Atherosclerosis

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] 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] Forearm plethysmography has replaced flow mediated dilation for assessing endothelial dysfunction.[18] von Willebrand factor is a marker of endothelial dysfunction and is consistently elevated in atrial fibrillation.[19]

A non-invasive, FDA-approved device for measuring endothelial function that works by measuring Reactive Hyperemia Index (RHI) is Itamar Medical's EndoPAT.[20][21] It has shown an 80% sensitivity and 86% specificity to diagnose coronary artery disease when compared against the gold standard, acetylcholine angiogram.[22] 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,[23] 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.[24] 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.[25]

### Endothelial dysfunction and stents

Stent implantation has been correlated with impaired endothelial function in several studies.[26] 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.[26] One drug used to inhibit restenosis is iopromide-paclitaxel.[27]

### COVID-19 complication in the lungs

COVID-19 can present with an acute lung injury manifestation that arises from endothelial dysfunction.[28]

### 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.[29][30] 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.[31]

## See also

* Atherosclerosis
* Endothelial activation
* Nitric oxide
* Endothelial nitric oxide synthase
* Prostacyclin
* Endothelium-derived relaxing factor
* Endothelin
* Integrin network
* Endothelial shear stress

## References

1. ↑ 1.0 1.1 "Targeting Early Atherosclerosis: A Focus on Oxidative Stress and Inflammation". Oxidative Medicine and Cellular Longevity 2019. 2019. doi:10.1155/2019/8563845. PMID 31354915.
2. ↑ Sitia, S.; Tomasoni, L.; Atzeni, F.; Ambrosio, G.; Cordiano, C.; Catapano, A.; Tramontana, S.; Perticone, F. et al. (2010). "From endothelial dysfunction to atherosclerosis". Autoimmunity Reviews 9 (12): 830–834. doi:10.1016/j.autrev.2010.07.016. PMID 20678595.
3. ↑ "The assessment of endothelial function: from research into clinical practice". Circulation 126 (6): 753–67. Aug 2012. doi:10.1161/circulationaha.112.093245. PMID 22869857. Bibcode: 2012Circu.126..753F.
4. ↑ 4.0 4.1 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" (in en). Viruses 13 (1): 29. doi:10.3390/v13010029. ISSN 1999-4915. PMID 33375371.
5. ↑ 5.0 5.1 5.2 5.3 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.
6. ↑ 6.0 6.1 "Functionally defective high-density lipoprotein and paraoxonase: a couple for endothelial dysfunction in atherosclerosis". Cholesterol 2013. 2013. doi:10.1155/2013/792090. PMID 24222847.
7. ↑ "Dysfunctional Vascular Endothelium as a Driver of Atherosclerosis: Emerging Insights Into Pathogenesis and Treatment". Frontiers in Pharmacology 12. December 2021. doi:10.3389/fphar.2021.787541. PMID 35002720.
8. ↑ "Pathophysiology, diagnosis and prognostic implications of endothelial dysfunction". Annals of Medicine 40 (3): 180–96. 2008. doi:10.1080/07853890701854702. PMID 18382884.
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.
10. ↑ 10.0 10.1 "Oxidized LDL and NO synthesis--Biomarkers of endothelial dysfunction and ageing". Mechanisms of Ageing and Development 151: 101–113. 2015. doi:10.1016/j.mad.2015.03.003. PMID 25804383.
11. ↑ "Mechanisms of Oxidized LDL-Mediated Endothelial Dysfunction and Its Consequences for the Development of Atherosclerosis". Frontiers in Cardiovascular Medicine 9. 2022. doi:10.3389/fcvm.2022.925923. 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. 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. 956. pp. 511–540. doi:10.1007/5584_2016_90. ISBN 978-3-319-44250-1.
14. ↑ 14.0 14.1 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. ↑ 15.0 15.1 "Endothelial dysfunction, endothelial nitric oxide bioavailability, tetrahydrobiopterin, and 5-methyltetrahydrofolate in cardiovascular disease. Where are we with therapy?". Microvascular Research 119: 7–12. 2018. 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. PMID 17376239.
17. ↑ "Assessment of flow-mediated dilation in humans: a methodological and physiological guideline". Am J Physiol Heart Circ Physiol 300 (1): H2–12. Jan 2011. doi:10.1152/ajpheart.00471.2010. PMID 20952670.
18. ↑ "Lycopene and Vascular Health". Frontiers in Pharmacology 9. 2018. doi:10.3389/fphar.2018.00521. PMID 29875663.
19. ↑ "Endothelial function in patients with atrial fibrillation". Annals of Medicine 52 (1–2): 1–11. 2020. doi:10.1080/07853890.2019.1711158. PMID 31903788.
20. ↑ "Assessment of peripheral vascular endothelial function in the ambulatory setting". Vasc. Med. 12 (1): 13–6. Feb 2007. doi:10.1177/1358863x06076227. PMID 17451088.
21. ↑ "Assessing endothelial vasodilator function with the Endo-PAT 2000". Journal of Visualized Experiments (44). October 2010. doi:10.3791/2167. PMID 20972417.
22. ↑ "Noninvasive identification of patients with early coronary atherosclerosis by assessment of digital reactive hyperemia". J Am Coll Cardiol 44 (11): 2137–41. Dec 2004. doi:10.1016/j.jacc.2004.08.062. PMID 15582310.
23. ↑ "Role of nitric oxide deficiency and its detection as a risk factor in pre-hypertension". JASH 1 (1): 45–56. 2007. doi:10.1016/j.jash.2006.11.002. PMID 20409832.
24. ↑ "Association of small artery elasticity with incident cardiovascular disease in older adults: the multiethnic study of atherosclerosis". Am J Epidemiol 174 (5): 528–36. 2011. doi:10.1093/aje/kwr120. PMID 21709134.
25. ↑ "Comprehensive noninvasive arterial vascular evaluation". Future Cardiology 5 (6): 573–9. 2009. doi:10.2217/fca.09.44. PMID 19886784.
26. ↑ 26.0 26.1 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. doi:10.1177/2041731417731546. PMID 28989698.
27. ↑ Unverdorben, Martin; Vallbracht, Christian; Cremers, Bodo; Heuer, Hubertus; Hengstenberg, Christian; Maikowski, Christian; Werner, Gerald S.; Antoni, Diethmar et al. (2009-06-16). "Paclitaxel-coated balloon catheter versus paclitaxel-coated stent for the treatment of coronary in-stent restenosis" (in en). Circulation 119 (23): 2986–2994. doi:10.1161/circulationaha.108.839282. ISSN 0009-7322. PMID 19487593.
28. ↑ 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. PMID 36253560.
29. ↑ "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. 2007. PMID 17583170.
30. ↑ "Endothelial dysfunction and atherosclerosis: focus on novel therapeutic approaches". Recent Pat Cardiovasc Drug Discov 7 (1): 21–32. Apr 2012. doi:10.2174/157489012799362386. PMID 22280336.
31. ↑ 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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