Endothelins are hormones that constrict blood vessels and increase blood pressure. When overactive, they can cause heart, lung, kidney disorders, and other serious diseases. Read on to learn more about endothelins and factors that increase or decrease them.
What Are Endothelins?
Endothelins are peptide hormones (chains of amino acids) that are very powerful blood vessel constrictors.
- Endothelin-1 (ET-1) – produced by blood vessel cells, white blood cells, and brain cells.
- Endothelin-2 (ET-2) – produced by gut cells.
- Endothelin-3 (ET-3) – produced in the lungs, gut, and brain.
To produce physical effects, endothelins bind to two types of receptors :
ET-1 reduces blood flow and constricts blood vessels in the kidneys through activation of ETA receptors. Conversely, ETB receptors dilate the blood vessels, therefore reducing blood pressure .
Finally, endothelins need to become activated to be effective. This activation is performed by 2 enzymes:
This collection of endothelins, receptors, and two peptidase enzymes make up the endothelin system .
Endothelin in Diseases and Disorders
1) Endothelin Can Cause High Blood Pressure
ET-1 can cause high blood pressure in both humans and animals. When endothelins bind to ETA receptors, this causes blood vessels to tighten (constrict). When they bind to ETB receptors, this relaxes (dilates) blood vessels. [5, 6].
Increased ET-1 levels are seen in salt-sensitive hypertension (high blood pressure), as well as moderate to severe hypertension. In these cases, endothelin receptor blockers reduce high blood pressure [7, 8].
Increased levels of ET-1 were also shown to promote enlargement (hypertrophy) of the blood vessels. The blood vessel walls become thicker, further contributing to high blood pressure .
A review showed that those with blood vessel tumors and severe hypertension had increased levels of ET-1, which decreased after removing the tumor .
2) Endothelin Exacerbates Pulmonary Hypertension
Endothelin-1 is found in high amounts in the lungs, where it is a strong vasoconstrictor. People with pulmonary hypertension (high blood pressure in the lungs) have higher levels of endothelin in lung arteries and in the blood [10, 10].
Mice with pulmonary hypertension from hypoxia (low oxygen levels) have high blood pressure in the lungs even when oxygen levels are returned to normal. However, these effects are even more severe in genetically-altered mice with higher levels of ET-1, showing that endothelin plays a major role in the development of pulmonary hypertension .
3) Endothelin Increases the Feeling of Pain
Endothelin-1 activates pain receptors (nociceptors), and high endothelin levels in the brain and spinal cord increase the effects of other pain-inducing chemicals. These effects occur via the ETA receptor [12, 13].
Stimulating ETB receptors can either increase or decrease pain, depending on where and how these receptors are activated .
A study on female rats showed that ET-1 increased heat-related pain, via both ETA and ETB receptors .
ETA receptor blockers reduce pain associated with inflammation. ETB receptors have the opposite effects of ETA receptors; therefore, activating ETB receptors may reduce pain and inflammation [16, 17].
Pain associated with nerve damage may be temporarily relieved with ETA receptor blockers, In this case, a combination of ETA and ETB receptor blockers was less effective than ETA receptor blockers alone [16, 17].
ETA receptor blockers have been shown to ease the pain associated with cancer .
4) Endothelin Increases Inflammation
The production of ET-1 leads to inflammation in the blood vessels.
Inflammatory cytokines increase the production of ET-1. ET-1 then increases the amount of other inflammatory cytokines (TNF-alpha) in inflammatory cells. This stimulates the surrounding and engulfing of these cells by other white blood cells, thus enhancing the inflammatory process .
A study on mice found that ET-1 production also plays a role in inflammatory skin diseases. Higher levels of ET-1 were found in chronic and more severe skin diseases. ET-1 alters the interaction between specific immune cells (dendritic and T-cells), which enhance skin inflammation .
5) Endothelin Contributes to Atherosclerosis (Hardening of the Arteries)
ET-1 causes blood vessel dysfunction and inflammation which can contribute to the buildup of plaque in the vessels, causing the arteries to harden .
A review showed that ET-1 levels were increased in patients with atherosclerosis. Inflammatory cells also alter the production and presence of ETA and ETB receptors, which may contribute to the hardening of the arteries .
A study on 35 patients with atherosclerosis showed that treatment with an ETA receptor blocker slows the buildup of plaque in the arteries .
6) Endothelin Production Is Associated with Heart Failure
High endothelin levels increase resistance to blood flow, change the structure of blood vessels, and cause inflammation, all of which are common symptoms of heart failure. Treatment with ETA receptor blockers increases the function of the left ventricle in patients with left-sided heart failure .
ET-1 enhances the survival of heart muscle cells. However, with increased levels, the size of the heart can become too large (hypertrophy) .
7) Endothelin Overproduction Can Cause Lung Disorders
Endothelins-1, 2, and 3 are all involved in the constriction of the airways, with ET-1 being the most powerful. This is controlled by interaction with the ETB receptor .
ET-1 plays a role in asthma by constricting airways and increasing inflammation in the lungs. This inflammation also leads to further increases in ET-1 levels, making the problem even worse. Both children and adults with asthma show significantly elevated ET-1 levels .
ET-1, as well as its receptors, are present in pulmonary tumors. The endothelin-converting enzyme has also been found in pulmonary tumors. Endothelin-1 may play a role in tumor growth and survival through angiogenesis (production of new blood vessels) .
8) Endothelin Contributes to Chronic Kidney Disease
By activating ETA receptors, endothelin causes cell damage, excess protein in the urine, and inflammation and tissue build-up, resulting in chronic kidney disease .
In chronic kidney disease, endothelin levels are increased in the glomeruli (the filtering units of the kidneys), which causes injury to kidney cells as well as long-term inflammation .
ET-1 also contributes to kidney disease by causing cells to multiply and accumulate, blocking up the kidney and impairing its function .
The endothelin system is also activated in polycystic kidney disease .
9) Endothelin Contributes to the Progression of Infectious Diseases
Endothelin plays a role in the development of sepsis and septic shock. In this disease, damage to blood vessels causes endothelin levels to increase, which in turn correlates with kidney and heart dysfunction in both children and adults [32, 33, 18].
Endothelin also contributes to the progression of pneumonia. ET-1 production is stimulated in the lungs by reduced oxygen flow and lung infection .
A study on 281 pneumonia patients showed an increase in ET-1 precursor peptides, indicating that ET-1 levels correlate with disease severity .
Increased levels of ET-1 also play a role in the development of brain infections, such as bacterial meningitis, malaria, and HIV encephalitis. Overproduction of ET-1 is linked to increased permeability of the blood-brain barrier and activation of brain cells (astrocytes) .
10) Endothelin Can Cause Insulin Resistance
A study showed that increased ET-1 production contributes to insulin resistance in patients with obesity and diabetes. Blocking endothelin receptors led to increased insulin-stimulated blood flow in the legs as well as better glucose absorption by the muscles .
11) High Endothelin Contributes to Diabetes
By constricting the blood vessels and reducing oxygen flow to tissues, ET-1 causes a decrease in glucose usage, therefore contributing to the development of type 2 diabetes .
In type 2 diabetes, the activity of ET-1 and ETA receptors is enhanced. Treatment with ETA receptor blockers corrects the defective blood vessel constriction in patients with diabetes .
12) Endothelin Promotes Cancer Growth
ET-1 promotes cell division (mitosis) and activates cancer-causing genes. ET-1 is also present in high concentrations in cancer cells and it is an essential hormone in the development and progression of several types of cancer including lung, breast, prostate, and colon cancer [23, 38].
The endothelin axis plays a major role in the progression of ovarian cancer. Activation of the ETA receptors leads to increases in tumor cell growth, angiogenesis (the creation of new blood vessels), and reduces tumor cell death (apoptosis), all of which makes the cancer more invasive and dangerous .
A review showed that an ETA receptor blocker was effective in treating prostate cancer .
Endothelin-1 and its receptors are increased in cancerous breast tissue compared to normal breast tissue. They are also found in higher amounts in malignant tissue than benign. This suggests that ET-1 contributes to the progression of breast cancer [42, 43, 44].
Overproduction of endothelin converting enzyme (ECE) also plays a role in breast cancer. Patients with tumors that had increased levels of ECE had a higher incidence of tumor recurrence and metastasis. Those whose tumors had lower levels of ECE had a higher chance of survival [45, 46].
When treated with ECE inhibitors, ET-1 was significantly reduced and breast tumors became less likely to spread .
13) Endothelin Can Exacerbate Brain Injury
Endothelin levels and ETA receptors appear to increase following a brain injury. This causes a decrease in blood flow to the brain and reduces the chance of a full recovery .
This effect has also been seen in children with traumatic brain injuries, who show elevated ET-1 levels in the brain and spinal fluid. ET-1 constricts the blood vessels, leading to low blood flow to the brain. This is sustained for at least 5 days after injury .
14) Endothelin Contributes to Preeclampsia
Dysfunction of the endothelin system contributes to the onset and development of preeclampsia (high blood pressure in pregnancy). Pregnant women with preeclampsia have higher levels of blood ET-1 compared to pregnant women without the disease [49, 50].
If abnormally developed, the placenta releases factors that prevent blood vessel formation (such as sFlt-1). These factors increase the production of ET-1, which can lead to preeclampsia [49, 51, 52, 50].
15) Endothelin in Systemic Sclerosis
Increased levels of ET-1 are seen in the blood, skin, and connective tissue cells of patients with systemic sclerosis. This causes the buildup of tissues and collagen (fibrosis) associated with the disorder .
Bosentan, a treatment for hypertension that blocks ETA and ETB receptors, reverses the production of excess tissue caused by ET-1 .
16) Endothelin in Periodontal Diseases
Endothelin also plays a role in periodontal disease.
Many different cells in the mouth produce ET-1, and its levels increase significantly in periodontal disease, either because of bacteria in the mouth or inflammation in gum tissue .
17) Endothelin Is High in Sickle Cell Disease
A review showed that sickle cell disease is accompanied by high levels of ET-1 in the blood and urine. Counteracting this by blocking endothelin receptors prevented kidney damage and urinary symptoms, reduced physical pain and prevented lung damage associated with the disease .
The Endothelin System Differs Between Men and Women
Men have higher levels of endothelin, and it also has stronger vasoconstrictive effects in males. This may explain why men are more likely than women to develop severe blood pressure problems, and why they get them earlier in life [58, 59].
In men, endothelin is also more likely to activate ET-1 and ETA receptors, whereas in women it more strongly affects ETB receptor activation. ETB activation reduces the chances of developing high blood pressure, further explaining why hypertension affects men more often .
Female sex hormones contribute to lower ET-1 levels. Increasing levels of male sex hormones are correlated with higher ET-1 levels .
Factors That Increase Endothelin
1) Cigarette Smoke
Cigarette smoke also increases the production of ETA and ETB receptors along with ET-1 in many different tissues. This ability to magnify the effects of endothelin is a major part of why smoking is so strongly linked to heart and lung disorders .
2) Air Pollution
There is a significant correlation between pollution exposure and endothelin levels. Pollution is known to negatively affect the heart and blood vessels, which is likely due to increasing ET-1 levels .
As we age, we become more likely to develop endothelial-related diseases. Aging also causes ET-1 production to increase and makes the endothelin system more active .
Another review showed that endothelial-related blood vessel constriction increases with age and can lead to the development of hypertension (high blood pressure) .
5) High Insulin
6) Being Overweight
A review found that obesity contributes to blood vessel disorders by increasing ET-1 levels and enhancing its constrictive effect .
8) Some Drugs
Some drugs increase ET-1 levels. For example, sunitinib (an anti-cancer drug) doubled ET-1 levels in patients after 4 weeks of treatment, and tripled levels in rats after 8 days .
Phototherapy (exposure to specific wavelengths of light) significantly increased ET-1 levels in 33 preterm infants .
Factors That Decrease Endothelin
1) Moderate Exercise
Three weeks of moderate exercise (Tai Chi) lowered ET-1 levels in 22 elderly subjects .
Aerobic exercise reduced ET-1 levels in trained men, but increased them in untrained men. This may be because of the stress exercise produces in an untrained body .
Similarly, ET-1 levels decreased in 20 healthy men after cycling, but increased after jogging .
Therefore, the intensity of exercise, as well as one’s overall level of fitness, may affect whether exercise increases or decreases endothelin levels.
2) Heat Therapy
A study of patients with peripheral artery disease (PAD) found that heat therapy is effective in reducing blood pressure and ET-1 levels, thus improving blood flow in the legs .
3) Citrus Flavonoids
4) Weight Loss
Patients with type II diabetes exhibited reduced ET-1 after weight loss .
7) Red Wine
ET-1 levels were reduced after consumption of either alcoholic or non-alcoholic red wine, but no blood pressure changes were seen .
Even just one treatment with a supplement containing 200mg of epicatechin reduced ET-1 levels in healthy men. This is the same amount that is normally found in a single serving of epicatechin-rich foods like chocolate and green tea .
L-arginine intravenous (IV) infusion reduced ET-1 levels in patients with angina (heart pain from lack of oxygen) .
Genistein decreased ET-1 levels in rats whose ovaries had been removed (to simulate menopause in women) .
Somatostatin lowered ET-1 levels and improved liver function in patients undergoing liver transplantation .
Pretreatment with ginkgo reduced ET-1 levels in animals with heart disease .
ET-1 levels were reduced by 6% in patients with heart disease treated with Ginkgo extract .
15) Red Sage
Estrogen counteracted the increase in ET-1 levels caused by angioplasty (the placement of a balloon in the arteries to improve blood flow) in patients undergoing the procedure. It also lessened the vasoconstrictive effects of ET-1 .
17) Olive Oil
Increased olive oil consumption in women with high blood pressure reduced ET-1 levels and ET-1 receptors .
19) Helicobacter pylori elimination
Removal of H. pylori bacteria from the gut reduced ET-1 levels in the blood in patients with gut ulcers .
20) Some Drugs
Patients treated with omalizumab (an IgE antibody) showed significantly reduced ET-1 levels .
One month of treatment with montelukast (an anti-asthma drug) reduced ET-1 levels in the blood of 36 children with mild asthma .
Acupuncture may reduce blood ET-1 levels and improve blood flow in patients who have reduced blood flow to the brain .
Endothelin Receptor Blockers
Endothelin-related diseases can be treated using endothelin receptor blockers (antagonists).
Bosentan, an ETA and ETB receptor blocker, reversed hypertension (high blood pressure) induced by low oxygen flow. It also reduced enlargement of the heart and remodeling of the arteries .
ETA receptor blockade is shown to increase blood flow to the kidneys. However, ETB receptor blockers had negative impacts on blood flow in patients with chronic kidney disease .
A review showed that ETB receptor blockades are more efficient in reducing the symptoms of sepsis. Treatment with ETB receptor blockades increased blood flow in the kidneys and reduced oxidative stress .
Endothelin receptor blockers may also help in:
- Sickle cell disease 
- Tissue damage/fibrosis 
- Brain injury 
- Hardening of the arteries (atherosclerosis) 
- Cancer 
- Opioid withdrawal 
The minor T variant is associated with:
- Asthma 
- Increased HDL cholesterol levels 
- Higher blood pressure in people who aren’t physically fit 
- Worsening of primary biliary cirrhosis 
- Hearing impairment in the elderly 
- Juvenile hypertension (high blood pressure) in obesity 
However, it may also increase the risk of asthma .
EDNRA produces the ETA receptor .
It may also decrease the risk of early-onset Hashimoto’s thyroiditis .
The EDNRB gene is responsible for producing ETB receptors .
This SNP is associated with an increased risk for hardening of the arteries in men with high blood pressure. Those with two A variants tend to develop mild or severe atherosclerosis (hardening of the arteries) .
AA and GA carriers more often had salt-resistant than salt-sensitive hypertension. Having two G variants (GG) is associated with increased risk of salt-sensitive hypertension .
ECE1 converts endothelin precursors to biologically active peptides .
The T variant is associated with lower enzyme production .
Women with two T variants (TT) have higher blood pressure .
ECE2 converts endothelin precursors to ET-1.
This SNP is associated with age at first menstruation and body mass index (BMI) in puberty .