Endothelial dysfunction

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Comparison of healthy vs. dysfunctional vascular endothelium Viruses-13-00029-g001.webp
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]

Contents

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

Atherosclerosis

Stages of endothelial dysfunction in atherosclerosis of arteries Atherosclerosis timeline - endothelial dysfunction.svg
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

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]

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

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

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

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. [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

Related Research Articles

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<span class="mw-page-title-main">Atherosclerosis</span> Inflammatory disease involving buildup of lesions in the walls of arteries

Atherosclerosis is a pattern of the disease arteriosclerosis, characterized by development of abnormalities called lesions in walls of arteries. This is a chronic inflammatory disease involving many different cell types, and driven by elevated levels of cholesterol in the blood. These lesions may lead to narrowing of the arterial walls due to buildup of atheromatous plaques. At onset there are usually no symptoms, but if they develop, symptoms generally begin around middle age. In severe cases, it can result in coronary artery disease, stroke, peripheral artery disease, or kidney disorders, depending on which body part(s) the affected arteries are located in the body.

<span class="mw-page-title-main">Endothelium</span> Layer of cells that line the inner surface of blood vessels

The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel wall.

<span class="mw-page-title-main">Restenosis</span> Recurrence of stenosis, a narrowing of a blood vessel

Restenosis is the recurrence of stenosis, a narrowing of a blood vessel, leading to restricted blood flow. Restenosis usually pertains to an artery or other large blood vessel that has become narrowed, received treatment to clear the blockage, and subsequently become re-narrowed. This is usually restenosis of an artery, or other blood vessel, or possibly a vessel within an organ.

<span class="mw-page-title-main">Coronary thrombosis</span> Medical condition

Coronary thrombosis is defined as the formation of a blood clot inside a blood vessel of the heart. This blood clot may then restrict blood flow within the heart, leading to heart tissue damage, or a myocardial infarction, also known as a heart attack.

<span class="mw-page-title-main">Haemodynamic response</span>

In haemodynamics, the body must respond to physical activities, external temperature, and other factors by homeostatically adjusting its blood flow to deliver nutrients such as oxygen and glucose to stressed tissues and allow them to function. Haemodynamic response (HR) allows the rapid delivery of blood to active neuronal tissues. The brain consumes large amounts of energy but does not have a reservoir of stored energy substrates. Since higher processes in the brain occur almost constantly, cerebral blood flow is essential for the maintenance of neurons, astrocytes, and other cells of the brain. This coupling between neuronal activity and blood flow is also referred to as neurovascular coupling.

<span class="mw-page-title-main">Tetrahydrobiopterin</span> Chemical compound

Tetrahydrobiopterin (BH4, THB), also known as sapropterin (INN), is a cofactor of the three aromatic amino acid hydroxylase enzymes, used in the degradation of amino acid phenylalanine and in the biosynthesis of the neurotransmitters serotonin (5-hydroxytryptamine, 5-HT), melatonin, dopamine, norepinephrine (noradrenaline), epinephrine (adrenaline), and is a cofactor for the production of nitric oxide (NO) by the nitric oxide synthases. Chemically, its structure is that of a (dihydropteridine reductase) reduced pteridine derivative (quinonoid dihydrobiopterin).

Vasospasm refers to a condition in which an arterial spasm leads to vasoconstriction. This can lead to tissue ischemia and tissue death (necrosis). Cerebral vasospasm may arise in the context of subarachnoid hemorrhage. Symptomatic vasospasm or delayed cerebral ischemia is a major contributor to post-operative stroke and death especially after aneurysmal subarachnoid hemorrhage. Vasospasm typically appears 4 to 10 days after subarachnoid hemorrhage.

<span class="mw-page-title-main">Endothelin</span>

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<span class="mw-page-title-main">Endothelial NOS</span> Protein and coding gene in humans

Endothelial NOS (eNOS), also known as nitric oxide synthase 3 (NOS3) or constitutive NOS (cNOS), is an enzyme that in humans is encoded by the NOS3 gene located in the 7q35-7q36 region of chromosome 7. This enzyme is one of three isoforms that synthesize nitric oxide (NO), a small gaseous and lipophilic molecule that participates in several biological processes. The other isoforms include neuronal nitric oxide synthase (nNOS), which is constitutively expressed in specific neurons of the brain and inducible nitric oxide synthase (iNOS), whose expression is typically induced in inflammatory diseases. eNOS is primarily responsible for the generation of NO in the vascular endothelium, a monolayer of flat cells lining the interior surface of blood vessels, at the interface between circulating blood in the lumen and the remainder of the vessel wall. NO produced by eNOS in the vascular endothelium plays crucial roles in regulating vascular tone, cellular proliferation, leukocyte adhesion, and platelet aggregation. Therefore, a functional eNOS is essential for a healthy cardiovascular system.

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References

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