Understanding the role of endothelin-1 (ET-1)

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Endothelin-1 (ET-1) is a peptide that plays a crucial role in regulating various physiological processes in the human body. It is primarily produced and secreted by endothelial cells, which are the cells that line the inner walls of blood vessels. ET-1 is a potent vasoconstrictor, meaning it causes blood vessels to constrict or narrow. ET-1 has been shown to be one of the most potent vasoconstrictors.¹

Vasoconstriction is mediated principally by ETA receptors on the underlying smooth muscle, where a small proportion of ETB receptors may also be present.¹ When ET-1 binds to these receptors, it leads to vasoconstriction. ETA receptor activation results in an increase in intracellular calcium levels within smooth muscle cells, which, in turn, causes the muscle cells to contract. This contraction narrows the blood vessel, leading to reduced blood flow through it.

However, there are multiple other biological effects of ET-1 that are recognised including immune regulation, vascular remodelling and fibrosis, while dysregulation of ET-1 and its related pathways have been causally identified as an important mediator in many diseases.¹ By understanding the science behind these mechanisms, we’re exploring new ways to slow or stop disease progression.

ET-1 and cardiovascular health

Dysregulation of ET-1 production and signalling has been implicated in various cardiovascular diseases, including hypertension, atherosclerosis, and heart failure.²

One of the primary roles of ET-1 is to regulate blood vessel tone. When ET-1 is released in response to various stimuli, such as injury or inflammation, it causes blood vessels to constrict. This constriction can increase blood pressure and reduce blood flow to specific tissues or organs, which can be beneficial in certain situations, such as limiting bleeding after an injury. However, excessive or chronic vasoconstriction can contribute to conditions like hypertension.

The potential for precision medicine with emerging genetic variants in the ET pathway

The PHACTR1 gene regulates the expression of the EDN1 gene – the gene responsible for encoding ET-1. Genome-wide association studies have linked angina and other cardiovascular diseases to a common functional single nucleotide polymorphism (SNP) – a genetic variation that can occur between individuals – in the PHACTR1 gene. This SNP is being exploited in a precision medicine trial to identify patients with the variant and enrich the study population, with participants most likely to benefit from ET receptor antagonism.¹

ET-1 and kidney health

The role of ET-1 in the development and progression of kidney disease is well established and is an area of ongoing research. ET-1 has clear roles in cell proliferation, podocyte dysfunction, inflammation and fibrosis. ETA receptor antagonism has been shown to improve renal blood flow and reduce glomerular pressure. It also reduces podocyte loss, mesangial expansion, and albuminuria.

ET-1 produced in nephrons of the kidney regulates sodium and water excretion and is therefore likely to be a contributing factor to the primary adverse effect associated with ET receptor antagonists, which is fluid retention. There is ongoing research to understand the mechanisms as there are several biological actions that may contribute.

ET-1 and liver health

The production of ET-1 is significantly upregulated in liver cirrhosis and contributes to the vasoconstriction within the liver that drives elevated portal pressure in cirrhosis.³ Elevated portal pressure leads to increased aldosterone levels via activation of the angiotensin system.^4,5 This is the main driver for fluid retention associated with portal hypertension.⁵

ETA receptor activation on hepatic vascular endothelial cells can lead to vasoconstriction of the blood vessels in the liver. This can impact blood flow within the liver and may be involved in regulating hepatic blood pressure.¹ In addition, ETA receptors have been implicated in developing liver fibrosis. Activation of these receptors can stimulate the production of extracellular matrix proteins, contributing to the formation of scar tissue in the liver.¹

Endothelin ETB receptors beneficially remove the ET-1/ETB complex through endocytosis, to limit vasoconstriction.¹

The challenge of complex diseases

It's important to note that while ET-1 serves many essential functions in the body, its dysregulation or overproduction can contribute to pathological conditions. Understanding the role of endothelin-1 is crucial for both basic science research and the development of therapeutic interventions in various diseases related to vascular function and inflammation. Researchers continue to study the intricate regulatory mechanisms of ET-1 and its potential as a therapeutic target.