Comparison of healthy vs. dysfunctional vascular endothelium

In vascular diseases, endothelial dysfunction is a systemic pathological state of the endothelium. Along with acting as a semi-permeable membrane, the endothelium is responsible for maintaining vascular tone and regulating oxidative stress by releasing mediators, such as nitric oxide, prostacyclin and endothelin, and controlling local angiotensin-II activity.[1][2]

A dysfunctional endothelium is characterized by vasoconstriction, increased vascular permeability, thrombosis, and inflammation. This pathological state is often accompanied by elevated levels of biomarkers such as prothrombin time, D-dimers, fibrin degradation products, C-reactive protein (CRP), ferritin, 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.[3]

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.[3]

Research

Atherosclerosis

Stages of endothelial dysfunction in atherosclerosis of arteries

Endothelial dysfunction may be involved in the development of atherosclerosis[4][5][6] and may predate vascular pathology.[4][7] Endothelial dysfunction can also lead to increased adherence of monocytes and macrophages, as well as promoting infiltration of LDL in the vessel wall.[8] Dyslipidemia and hypertension are well known to contribute to endothelial dysfunction,[9][10] and lowering blood pressure and LDL has been shown to improve endothelial function, particularly when lowered with ACE inhibitors, calcium channel blockers, and statins.[11]

Nitric oxide

Nitric oxide (NO) suppresses platelet aggregation, inflammation, oxidative stress, vascular smooth muscle cell migration and proliferation, and leukocyte adhesion.[5] 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,[4] 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.

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.[4]

A non-invasive method to measure endothelial dysfunction is % Flow-Mediated Dilation (FMD) as measured by Brachial Artery Ultrasound Imaging (BAUI).[12] 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.[13]

A non-invasive, FDA-approved device for measuring endothelial function that works by measuring Reactive Hyperemia Index (RHI) is Itamar Medical’s EndoPAT.[14][15] It has shown an 80% sensitivity and 86% specificity to diagnose coronary artery disease when compared against the gold standard, acetylcholine angiogram.[16] 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,[17] 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.[18] 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.[19]

Endothelial dysfunction and stents

Stent implantation has been correlated with impaired endothelial function in several studies.[20] 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.[20] One drug used to inhibit restenosis is iopromide-paclitaxel.[21]

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.[22][23] Calcium channel blockers and selective beta 1 antagonists may also improve endothelial dysfunction.[11] Life style modifications such as smoking cessation have also been shown to improve endothelial function and lower the risk of major cardiovascular events.[24]

See also

References

  1. ↑ 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.
  2. ↑ 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.
  3. 1 2 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.
  4. 1 2 3 4 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.
  5. 1 2 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.
  6. ↑ Botts SR, Fish JE, Howe KL (December 2021). "Dysfunctional Vascular Endothelium as a Driver of Atherosclerosis: Emerging Insights Into Pathogenesis and Treatment". Frontiers in Pharmacology. 12: 787541. doi:10.3389/fphar.2021.787541. PMC 8727904. PMID 35002720.
  7. ↑ Münzel T, Sinning C, Post F, Warnholtz A, Schulz E (2008). "Pathophysiology, diagnosis and prognostic implications of endothelial dysfunction". Annals of Medicine. 40 (3): 180–96. doi:10.1080/07853890701854702. PMID 18382884. S2CID 18542183.
  8. ↑ 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. S2CID 71334997.
  9. ↑ 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.
  10. ↑ Konukoglu, Dildar; Uzun, Hafize (2017). "Endothelial Dysfunction and Hypertension". Hypertension: From basic research to clinical practice. Advances in Experimental Medicine and Biology. Vol. 956. pp. 511–540. doi:10.1007/5584_2016_90. ISBN 978-3-319-44250-1. ISSN 0065-2598. PMID 28035582.
  11. 1 2 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.
  12. ↑ 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. PMC 1847451. PMID 17376239.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ Axtell AL, Gomari FA, Cooke JP (October 2010). "Assessing endothelial vasodilator function with the Endo-PAT 2000". Journal of Visualized Experiments (44). doi:10.3791/2167. PMC 3143035. PMID 20972417.
  16. ↑ Bonetti PO, Pumper GM, Higano ST, Holmes DR Jr, Kuvin JT, Lerman A (Dec 2004). "Noninvasive identification of patients with early coronary atherosclerosis by assessment of digital reactive hyperemia". J Am Coll Cardiol. 44 (11): 2137–41. doi:10.1016/j.jacc.2004.08.062. PMID 15582310.
  17. ↑ Gilani M, Kaiser DR, Bratteli CW, Alinder C, Rajala Bank AJ, Cohn JN (2007). "Role of nitric oxide deficiency and its detection as a risk factor in pre-hypertension". JASH. 1 (1): 45–56. doi:10.1016/j.jash.2006.11.002. PMID 20409832.
  18. ↑ 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.
  19. ↑ 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.
  20. 1 2 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.
  21. ↑ 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.
  22. ↑ 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.
  23. ↑ 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.
  24. ↑ 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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