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Endothelial dysfunction

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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

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Atherosclerosis

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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

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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

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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.[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

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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

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

Risk reduction

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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

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References

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  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.
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  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.
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  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.
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  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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