In blood vessel diseases, endothelial dysfunction is an unhealthy state of the the cells that line the blood vessels (endothelium). The main cause of endothelial dysfunction is impaired bioavailability of

nitric oxide Nitric oxide (nitrogen oxide, nitrogen monooxide, or nitrogen monoxide) is a colorless gas with the formula . It is one of the principal oxides of nitrogen. Nitric oxide is a free radical: it has an unpaired electron, which is sometimes den ...

. In addition to acting as a

semipermeable membrane Semipermeable membrane is a type of synthetic or biologic, polymeric membrane that allows certain molecules or ions to pass through it by osmosis. The rate of passage depends on the pressure, concentration, and temperature of the molecules o ...

, the endothelium is responsible for maintaining

vascular tone Vascular resistance is the resistance that must be overcome for blood to flow through the circulatory system. The resistance offered by the systemic circulation is known as the systemic vascular resistance or may sometimes be called by another ter ...

and regulating

oxidative stress Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal ...

by releasing mediators, such as nitric oxide,

prostacyclin Prostacyclin (also called prostaglandin I2 or PGI2) is a prostaglandin member of the eicosanoid family of lipid molecules. It inhibits platelet activation and is also an effective vasodilator. When used as a drug, it is also known as epoprosteno ...

and endothelin, and by controlling local

angiotensin Angiotensin is a peptide hormone that causes vasoconstriction and an increase in blood pressure. It is part of the renin–angiotensin system, which regulates blood pressure. Angiotensin also stimulates the release of aldosterone from the adr ...

-II activity. Dysfunctional endothelium is characterized by constricted blood vessels, increased ability of chemicals to flow through blood vessel walls,

blood clots A thrombus ( thrombi) is a solid or semisolid aggregate from constituents of the blood (platelets, fibrin, red blood cells, white blood cells) within the circulatory system during life. A blood clot is the final product of the blood coagulati ...

, and

inflammation Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...

. This pathological state is often associated with elevated levels of

biomarker In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, ...

s such as

prothrombin time The prothrombin time (PT) – along with its derived measures of prothrombin ratio (PR) and international normalized ratio (INR) – is an assay for evaluating the Coagulation#Extrinsic pathway, extrinsic pathway and Coagulation#Common pathway, ...

D-dimer D-dimer (or D dimer) is a dimer that is a fibrin degradation product (FDP), a small protein fragment present in the blood after a blood clot is degraded by fibrinolysis. It is so named because it contains two D fragments of the fibrin protein ...

von Willebrand factor Von Willebrand factor (VWF) () is a blood glycoprotein that promotes primary hemostasis, specifically, platelet adhesion. It is deficient and/or defective in von Willebrand disease and is involved in many other diseases, including thrombotic thro ...

, fibrin degradation products,

C-reactive protein C-reactive protein (CRP) is an annular (ring-shaped) pentameric protein found in blood plasma, whose circulating concentrations rise in response to inflammation. It is an acute-phase protein of hepatic origin that increases following interleukin ...

(CRP),

ferritin Ferritin is a universal intracellular and extracellular protein that stores iron and releases it in a controlled fashion. The protein is produced by almost all living organisms, including archaea, bacteria, algae, higher plants, and animals. ...

Interleukin 6 Interleukin 6 (IL-6) is an interleukin that acts as both a pro-inflammatory cytokine and an anti-inflammatory myokine. In humans, it is encoded by the ''IL6'' gene. In addition, osteoblasts secrete IL-6 to stimulate osteoclast formation. Smoo ...

(IL-6), and plasma

creatinine Creatinine (; ) is a breakdown product of creatine phosphate from muscle and protein metabolism. It is released at a constant rate by the body (depending on muscle mass). Biological relevance Serum creatinine (a blood measurement) is an impor ...

. The result of this endothelial dysregulation is a cascade of harmful effects, including tightened blood vessels, small blood vessel leakage, blood clots, high levels of inflammation, and a disrupted

immune response An immune response is a physiological reaction which occurs within an organism in the context of inflammation for the purpose of defending against exogenous factors. These include a wide variety of different toxins, viruses, intra- and extracellula ...

against

virus A virus is a submicroscopic infectious agent that replicates only inside the living Cell (biology), cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea. Viruses are ...

es. These changes contribute to the progression of blood vessel (vascular) diseases. In a healthy state, the endothelium exhibits wider blood vessels, tightly-controlled blood vessel permeability, and anti-thrombotic and anti-inflammatory properties. This balance ensures the smooth functioning of the vascular system.

Research

Atherosclerosis

Endothelial dysfunction may be involved in the development of

atherosclerosis 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 is driven by eleva ...

and may predate vascular pathology. Endothelial dysfunction may also lead to increased adherence of

monocyte Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and monocyte-derived dendritic cells. As a part of the vertebrate innate immune system monocytes also ...

s and

macrophage Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...

s, as well as promoting infiltration of

low-density lipoprotein Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein that transport all fat molecules around the body in extracellular water. These groups, from least dense to most dense, are chylomicrons (aka ULDL by the overall density ...

(LDL) in the vessel wall. Oxidized LDL is a hallmark feature of atherosclerosis, by promoting the formation of foam cells,

chemotaxis Chemotaxis (from ''chemical substance, chemo-'' + ''taxis'') is the movement of an organism or entity in response to a chemical stimulus. Somatic cells, bacteria, and other single-cell organism, single-cell or multicellular organisms direct thei ...

, and platelet activation, leading to

atheromatous plaque An atheroma, or atheromatous plaque, is an abnormal accumulation of material in the inner layer of an arterial wall. The material consists of mostly macrophage cells, or debris, containing lipids, calcium and a variable amount of fibrous conne ...

instability and ultimately to rupture.

Dyslipidemia Dyslipidemia is a metabolic disorder characterized by abnormally high or low amounts of any or all lipids (e.g. fats, triglycerides, cholesterol, phospholipids) or lipoproteins in the blood. Dyslipidemia is a risk factor for the development of ...

and

hypertension Hypertension, also known as high blood pressure, is a Chronic condition, long-term Disease, medical condition in which the blood pressure in the artery, arteries is persistently elevated. High blood pressure usually does not cause symptoms i ...

are well known to contribute to endothelial dysfunction, and lowering blood pressure and LDL has been shown to improve endothelial function, particularly when lowered with

ACE inhibitor Angiotensin-converting-enzyme inhibitors (ACE inhibitors) are a class of medication used primarily for the treatment of high blood pressure and heart failure. This class of medicine works by causing relaxation of blood vessels as well as a decr ...

calcium channel blocker Calcium channel blockers (CCB), calcium channel antagonists or calcium antagonists are a group of medications that disrupt the movement of calcium () through calcium channels. Calcium channel blockers are used as antihypertensive drugs, i.e., as ...

s, and

statin Statins (or HMG-CoA reductase inhibitors) are a class of medications that lower cholesterol. They are prescribed typically to people who are at high risk of cardiovascular disease. Low-density lipoprotein (LDL) carriers of cholesterol play ...

s. Steady laminar flow with high shear stress in blood vessels protects against atherosclerosis, whereas disturbed flow promotes atherosclerosis.

Nitric oxide

Nitric oxide (NO) suppresses platelet aggregation, inflammation, oxidative stress, vascular smooth muscle cell migration and proliferation, and leukocyte adhesion. A feature of endothelial dysfunction is the inability of

arteries An artery () is a blood vessel in humans and most other animals that takes oxygenated blood away from the heart in the systemic circulation to one or more parts of the body. Exceptions that carry deoxygenated blood are the pulmonary arteries in ...

and

arterioles An arteriole is a small-diameter blood vessel in the microcirculation that extends and branches out from an artery and leads to capillaries. Arterioles have muscular walls (usually only one to two layers of smooth muscle cells) and are the pr ...

to dilate fully in response to an appropriate stimulus, such as exogenous

nitroglycerine Nitroglycerin (NG) (alternative spelling nitroglycerine), also known as trinitroglycerol (TNG), nitro, glyceryl trinitrate (GTN), or 1,2,3-trinitroxypropane, is a dense, colorless or pale yellow, oily, explosive liquid most commonly produced by ...

, that stimulates release of

vasodilators Vasodilation, also known as vasorelaxation, is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. Blood vessel wal ...

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 Oxygen is a chemical element; it has chemical symbol, symbol O and atomic number 8. It is a member of the chalcogen group (periodic table), group in the periodic table, a highly reactivity (chemistry), reactive nonmetal (chemistry), non ...

species. As a co-factor for nitric oxide synthase,

tetrahydrobiopterin Tetrahydrobiopterin (BH4, THB), also known as sapropterin ( INN), is a cofactor of the three aromatic amino acid hydroxylase enzymes, used in the metabolism of amino acid phenylalanine and in the biosynthesis of the neurotransmitters serotoni ...

(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.

Testing and diagnosis

In the

coronary circulation Coronary circulation is the Circulatory system#Coronary vessels, circulation of blood in the arteries and veins that supply the cardiac muscle, heart muscle (myocardium). Coronary arteries supply oxygen saturation (medicine), oxygenated blood to ...

angiography Angiography or arteriography is a medical imaging technique used to visualize the inside, or lumen, of blood vessels and organs of the body, with particular interest in the arteries, veins, and the heart chambers. Modern angiography is perfo ...

coronary artery The coronary arteries are the arterial blood vessels of coronary circulation, which transport oxygenated blood to the heart muscle. The heart requires a continuous supply of oxygen to function and survive, much like any other tissue or organ of ...

responses to vasoactive agents may be used to test for endothelial function, and venous occlusion plethysmography and

ultrasonography Medical ultrasound includes diagnostic techniques (mainly imaging) using ultrasound, as well as therapeutic applications of ultrasound. In diagnosis, it is used to create an image of internal body structures such as tendons, muscles, joints, ...

are used to assess endothelial function of peripheral vessels in humans. A non-invasive method to measure endothelial dysfunction is % Flow-Mediated Dilation (FMD) as measured by Brachial Artery Ultrasound Imaging (BAUI). 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.

is a marker of endothelial dysfunction and is consistently elevated in

atrial fibrillation Atrial fibrillation (AF, AFib or A-fib) is an Heart arrhythmia, abnormal heart rhythm (arrhythmia) characterized by fibrillation, rapid and irregular beating of the Atrium (heart), atrial chambers of the heart. It often begins as short periods ...

. A non-invasive,

FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

-approved device for measuring endothelial function that works by measuring Reactive Hyperemia Index (RHI) is Itamar Medical's EndoPAT. It has shown an 80% sensitivity and 86% specificity to diagnose

coronary artery disease Coronary artery disease (CAD), also called coronary heart disease (CHD), or ischemic heart disease (IHD), is a type of cardiovascular disease, heart disease involving Ischemia, the reduction of blood flow to the cardiac muscle due to a build-up ...

when compared against the gold standard, acetylcholine angiogram. This result 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, 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. 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.

Endothelial dysfunction and stents

Stent In medicine, a stent is a tube usually constructed of a metallic alloy or a polymer. It is inserted into the Lumen (anatomy), lumen (hollow space) of an anatomic vessel or duct to keep the passageway open. Stenting refers to the placement of ...

implantation has been correlated with impaired endothelial function in several studies. Sirolimus eluting stents were previously used because they showed low rates of in-stent

restenosis 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 ...

, but further investigation showed that they often impair endothelial function in humans and worsen conditions. One drug used to inhibit restenosis is iopromide-

paclitaxel Paclitaxel, sold under the brand name Taxol among others, is a chemotherapy medication used to treat ovarian cancer, esophageal cancer, breast cancer, lung cancer, Kaposi's sarcoma, cervical cancer, and pancreatic cancer. It is administered b ...

COVID-19 complication in the lungs

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

Risk reduction

Treatment of

high blood pressure Hypertension, also known as high blood pressure, is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms itself. It is, however, a major ri ...

and high levels of cholesterol in the blood may improve endothelial function in people taking

statins Statins (or HMG-CoA reductase inhibitors) are a class of medications that lower cholesterol. They are prescribed typically to people who are at high risk of cardiovascular disease. Low-density lipoprotein (LDL) carriers of cholesterol play ...

(HMGCoA-reductase inhibitor), and

renin Renin ( etymology and pronunciation), also known as an angiotensinogenase, is an aspartic protease protein and enzyme secreted by the kidneys that participates in the body's renin-angiotensin-aldosterone system (RAAS)—also known as the reni ...

system inhibitors, such as

ACE inhibitors Angiotensin-converting-enzyme inhibitors (ACE inhibitors) are a class of medication used primarily for the treatment of hypertension, high blood pressure and heart failure. This class of medicine works by causing relaxation of blood vessels as ...

and

angiotensin II receptor antagonists Angiotensin II receptor blockers (ARBs), formally angiotensin II receptor type 1 (AT1) antagonists, also known as angiotensin receptor blockers, angiotensin II receptor antagonists, or AT1 receptor antagonists, are a group of pharmaceuticals tha ...

. Calcium channel blockers and selective beta 1 antagonists may also improve endothelial dysfunction. Lifestyle modifications such as

smoking cessation Smoking cessation, usually called quitting smoking or stopping smoking, is the process of discontinuing tobacco smoking. Tobacco smoke contains nicotine, which is Addiction, addictive and can cause Substance dependence, dependence. As a resu ...

have also been shown to improve endothelial function and lower the risk of major cardiovascular events.

References

{{Authority control Vascular diseases