The structure of the endothelium and the onset of microvascular endothelial dysfunction
The endothelium is composed of a single layer of endothelial cells. It functions as a selective barrier that separates blood content from the interstitial compartments. The endothelium plays a critical role in the homeostatic regulation of vascular tone, structure, coagulation of blood, and the trafficking of leukocytes for antigen presentation. The endothelium is also implicated in the catabolism of lipoproteins and other blood-borne molecules.
The endothelium integrates in response to several internal and external signals. These include pressure and sheer stress (mechanical stimuli), hormones, and locally secreted substances (hormonal stimuli). The endothelium itself is capable of releasing factors that modulate vascular tone. These are:
· Endothelium derived relaxing factors (EDFRs): Nitric oxide, and prostacyclin
· Endothelium-derived hyperpolarizing factor (EDHF)
· Endothelium-derived contracting factors (EDCFs): Agiotensin II, endothelin 1 and vasoconstrictor prostanoids
Endothelium dysfunction describes a state of non-optimal control of vascular tone and structure characterized by impaired or lost homeostatic mechanisms. This state results in the increased expression of adhesion molecules, an increase in oxidative stress, increased production of prothrombotic and proinflammatory factors, an increase in the proliferation of the vascular smooth muscle cell, and increased vascular smooth muscle tone that occurs secondary to the disrupted synthesis of EDFRs and overproduction of EDCFs.
Dysfunction occurs after endothelial activation, during which the expression of endothelial cell surface adhesions molecules such as vascular cell adhesion molecule 1 (VCAM1), intercellular adhesion molecule 1 (ICAM1), and endothelial leukocyte adhesion molecule (E-selectin) occurs. The induction of endothelial cell activation occurs via the action of proinflammatory cytokines, including TNF and IL-6; this causes the recruitment of circulating leukocytes. This can be exacerbated by endothelial dysfunction; therefore, endothelial activation is both caused by and produced as a result of endothelial dysfunction.
What are the consequences of microvascular endothelial dysfunction?
Endothelial dysfunction is commonly associated with several diseases linked to high cardiovascular risk. These include diabetes, dyslipidemia, aging, obesity, and hypertension. Endothelial dysfunction is systemic and arises from exposure to traditional and non-traditional risk factors.
Traditional risk factors include internal stimuli such as sheer stress and genetic factors. The systemic manifestations of microvascular under serial dysfunction affect morbidity and mortality; as such, endothelial dysfunction is considered a critical marker of total cardiovascular risk.
The relationship between microvascular and macrovascular endothelial dysfunction
There is a weak correlation between microvascular and macrovascular endothelial dysfunction in the general population, suggesting that both dysfunctions arise through unique pathological mechanisms and play a distinct role in determining the cause of vascular disease.
This is particularly true as the structure and function of the endothelial cells in the micro and macro vasculature are different. For example, as the size of arteries decreases, the relative role of nitric oxide in causing endothelium dependant vasodilation decreases, and the contribution played by EDHF for the same process increases.
Likewise, response to proinflammatory cytokines, expression of adhesion molecules and proteolytic enzymes, and the nitric oxide production also differs between different types of vascular beds - and between the micro and macro vasculature.
In the microvasculature, endothelial cells play a more critical role in leukocyte trafficking and inflammation. The microvasculature also covers a substantially larger area, i.e., 261,337 cm² in the arterioles and 879,989 cm² in the venules vs. 156 cm² in the aorta and 3,333 cm² in the larger arteries.
Consistent with the observation that microvascular versus microvascular endothelial dysfunction plays a critical role in cardiovascular risk, its association with future cardiovascular events was observed in a large cohort of 1574 healthy middle-aged men (49.9 years).
Moreover, the addition of microvascular to my risk model, which includes the Framingham risk score improved the risk and reclassification of all major cardiovascular events. The Framingham risk score is an algorithm used to estimate the risk of developing coronary heart disease in 10 years and is based on age, sex, blood pressure, treatment for high blood pressure, cholesterol levels, diabetes, and smoking status.
Moreover, vascular function appears to be a good predictor of cardiovascular events in patients without pre-existing vascular pathology; conversely, macrovascular endothelial dysfunction is a good predictor of cardiovascular events in patients with pre-existing atherosclerosis
References
· Rajendran P, Rengarajan T, Thangavel J, et al. (2013) The vascular endothelium and human diseases. Int J Biol Sci. doi:10.7150/ijbs.7502.
· Bordy R, Totoson P, Prati C, et al. (2018) Microvascular endothelial dysfunction in rheumatoid arthritis. Nat Rev Rheumatol. doi: 10.1038/s41584-018-0022-8.
· Widmer RJ, Lerman A. (2014) Endothelial dysfunction and cardiovascular disease. Glob Cardiol Sci Pract. doi:10.5339/gcsp.2014.43.
By Hidaya Aliouche, B.Sc.Reviewed by Danielle Ellis, B.Sc.
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