Endothelial Dysfunction - Diseases and Causes

Endothelial Dysfunction – Diseases, Causes & Promoters

Dicken Weatherby, N.D. and Beth Ellen DiLuglio, MS, RDN, LDN

Endothelial dysfunction refers to the functional and structural damage that occurs to the endothelium. With that damage, you will see a pro-inflammatory and pro-thrombotic state along with progressively reduced vasodilation in affected blood vessels.[i]

 Endothelial dysfunction and impaired vasodilation are also characteristic of diabetes and hypertension, revealing a “common enemy” among prevalent chronic “diseases.”[ii]

Diseases associated with endothelial dysfunction

  • Atherosclerosis - Endothelial dysfunction is damage to the endothelial lining of the artery and is thought to be a key event in the progression to atherosclerosis.
  • Heart attacks and stroke - endothelial dysfunction has been shown to be of prognostic significance in predicting vascular events including stroke and heart attacks.
  • Diabetes - Endothelial dysfunction may be a hallmark of hypertension and diabetes[iii]
  • Congestive heart failure (CHF)- Elevated inflammatory markers associated with endothelial dysfunction (CRP, TNF-alpha, von Willebrand factor, fibrinogen) may promote CHF.[iv]

Causes of endothelial dysfunction

Traditional and contemporary risk factors for cardiovascular disease and atherosclerosis are found to be directly associated with endothelial dysfunction:[v] [vi]

  • Adhesion molecule expression
  • Arterial hypertension
  • BMI (elevated)
  • Cigarette smoking
  • Diabetes
  • Dyslipidemia
  • Hyperglycemia
  • Hypertension
  • Insulin resistance
  • Metabolic syndrome
  • Oxidized low density lipoprotein
  • Proinflammatory cytokines
  • Renin-angiotensin axis

Additional promoters of endothelial dysfunction include:

  • Poor diet
  • Nutrient deficiencies
  • Lack of exercise, sedentary lifestyle
  • Increased Homocysteine
    • Homocysteine is dangerous because it can induce initial injury to the endothelium, then facilitate the oxidation of the fat/LDL that accumulates beneath the damaged endothelium, and finally contribute to the abnormal accumulation of blood components around the atherosclerotic lesion.[vii] [viii]
  • Hyperglycemia
    • Endothelial cells are highly metabolic and take up circulating glucose via Glut-1 transporter without the need for insulin.
    • Levels of glucose uptake by endothelial cells reflects circulating glucose levels without any impact from insulin sensitivity.
    • Circulating advanced glycation end-products (AGEs) correlate with atherosclerosis and arterial stiffness in those with coronary artery disease[ix]
    • Aortic stiffness was associated with endothelial dysfunction in those with hypertension and diabetes, but not in hypertension without diabetes[x]
    • Endothelial dysfunction may contribute to development of type 2 diabetes and may be present before overt hyperglycemia is detected[xi]
  • Increased fibrinogen synthesis
    • Fibrinogen contributes to the clotting process, further jeopardizing the integrity and function of the blood vessel
  • Elevated C-reactive protein (CRP)
    • CRP is a sign of inflammation and may actually damage the endothelium.[xii]
    • C-reactive protein may promote production of growth differentiation factor 15 (CD15), a molecule being researched for its potential as an independent biomarker of cardiovascular disease.[xiii]

Research

[i] Zehr, Kayla R, and Mary K Walker. “Omega-3 polyunsaturated fatty acids improve endothelial function in humans at risk for atherosclerosis: A review.” Prostaglandins & other lipid mediators vol. 134 (2018): 131-140. 

[ii] Bendall, Jennifer K et al. “Tetrahydrobiopterin in cardiovascular health and disease.” Antioxidants & redox signaling vol. 20,18 (2014): 3040-77. 

[iii] Bendall, Jennifer K et al. “Tetrahydrobiopterin in cardiovascular health and disease.” Antioxidants & redox signaling vol. 20,18 (2014): 3040-77. 

[iv] Vila, Virtudes et al. “Inflammation, endothelial dysfunction and angiogenesis markers in chronic heart failure patients.” International journal of cardiology vol. 130,2 (2008): 276-7. 

[v] Sitia, S et al. “From endothelial dysfunction to atherosclerosis.” Autoimmunity reviews vol. 9,12 (2010): 830-4. 

[vi] Zehr, Kayla R, and Mary K Walker. “Omega-3 polyunsaturated fatty acids improve endothelial function in humans at risk for atherosclerosis: A review.” Prostaglandins & other lipid mediators vol. 134 (2018): 131-140. 

[vii] Coppola, A et al. “Homocysteine, coagulation, platelet function, and thrombosis.” Seminars in thrombosis and hemostasis vol. 26,3 (2000): 243-54. 

[viii] Esse, Ruben et al. “The Contribution of Homocysteine Metabolism Disruption to Endothelial Dysfunction: State-of-the-Art.” International journal of molecular sciences vol. 20,4 867. 17 Feb. 2019.

[ix] McNulty, Marie et al. “Advanced glycation end-products and arterial stiffness in hypertension.” American journal of hypertension vol. 20,3 (2007): 242-7. 

[x] Bruno, R M et al. “Type 2 diabetes mellitus worsens arterial stiffness in hypertensive patients through endothelial dysfunction.” Diabetologia vol. 55,6 (2012): 1847-55. 

[xi] Bakker, Wineke et al. “Endothelial dysfunction and diabetes: roles of hyperglycemia, impaired insulin signaling and obesity.” Cell and tissue research vol. 335,1 (2009): 165-89. 

[xii] Suh, Wonhee et al. “C-reactive protein impairs angiogenic functions and decreases the secretion of arteriogenic chemo-cytokines in human endothelial progenitor cells.” Biochemical and biophysical research communications vol. 321,1 (2004): 65-71.

[xiii] Kim, Yoonseo et al. “CRP Stimulates GDF15 Expression in Endothelial Cells through p53.” Mediators of inflammation vol. 2018 8278039. 3 Jun. 2018.

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