Endothelin is a family of small peptides, each just 21 amino acids long, that rank among the most powerful blood-vessel-constricting substances the human body produces. First identified in 1988, the best-known member, endothelin-1 (ET-1), was originally described as a product of the cells lining blood vessels, but researchers now recognize it as something closer to a local hormone with fingers in nearly every organ system.1PubMed. Endothelin: 30 Years From Discovery to Therapy Understanding what endothelin does in healthy tissue, and what goes wrong when the system overproduces it, sheds light on conditions as varied as high blood pressure, kidney failure, and certain cancers.
How Endothelin Was Discovered
In 1988, the Japanese pharmacologist Masashi Yanagisawa and colleagues isolated a peptide from the culture fluid of pig aortic endothelial cells that caused extraordinarily strong, long-lasting contraction of blood vessel walls. They named it endothelin. Within a year, the same group and others had identified three distinct forms encoded by three separate genes.2PubMed Central. The human endothelin family: three structurally and pharmacologically distinct isopeptides predicted by three separate genes All three caused vasoconstriction and raised blood pressure when injected into animals, but their potency profiles differed enough to suggest that multiple receptor types existed. That hunch proved correct, and the field quickly expanded from a curiosity about a single vasoconstrictor into a broad area of cardiovascular and renal research.
Three Isoforms, Two Receptors
The endothelin family consists of endothelin-1, endothelin-2, and endothelin-3. ET-1 is by far the most abundant and best studied; it is produced mainly by endothelial cells throughout the vasculature but also by kidney cells, neurons, and other tissues.3PubMed. The discovery, the present state, and the future prospects of endothelin ET-2 is found in smaller quantities in the intestine and ovary, while ET-3 appears primarily in the brain and gut. Despite their structural similarity, the three peptides interact with the endothelin receptor system differently. ET-1 and ET-2 bind to both the ETA and ETB receptor subtypes with roughly equal strength, whereas ET-3 has a much weaker grip on the ETA receptor.4PubMed Central. Endothelin
Those two receptors usually pull in opposite directions. ETA receptors, found predominantly on smooth-muscle cells in vessel walls, drive vasoconstriction, cell growth, and inflammation. ETB receptors, concentrated on endothelial cells, tend to promote vasodilation, help clear circulating ET-1 from the blood, encourage sodium excretion, and counteract growth signals.5PubMed Central. Contrasting actions of endothelin ET(A) and ET(B) receptors in cardiovascular disease The balance between these two receptor pathways is central to understanding why endothelin can be both a normal physiological regulator and a driver of disease. When the system is in equilibrium, ETB-mediated nitric oxide release offsets ETA-mediated constriction.6PubMed. ETA and ETB receptors mediate contraction to endothelin-1 in renal artery of aging SHR When that balance tips toward ETA dominance, trouble follows.
How the Body Makes Endothelin
Endothelin-1 is not stored and released on demand the way some hormones are. Instead, production is mainly controlled at the gene-transcription level: when certain signals arrive, cells ramp up the message to build more ET-1. The initial gene product is a large, inactive precursor called preproendothelin. Enzymes clip it first into a slightly smaller intermediate called big ET-1, which itself has very little biological activity. A specialized enzyme, endothelin-converting enzyme (ECE), then performs a critical final cut to yield the mature 21-amino-acid peptide.7PubMed. Endothelin-1: Biosynthesis, Signaling and Vasoreactivity This multi-step processing means the body has several checkpoints where it can dial production up or down, which becomes relevant in disease states where those controls fail.
What Endothelin Does in a Healthy Body
People sometimes hear “vasoconstrictor” and assume endothelin’s sole job is squeezing blood vessels. In reality, ET-1 participates in a surprisingly wide range of housekeeping tasks.
Blood Pressure and Vascular Tone
ET-1 helps maintain baseline vascular tone, the slight tension in artery walls that keeps blood flowing at the right pressure. Through the interplay of ETA and ETB receptors, endothelin fine-tunes how tightly or loosely vessel walls contract at any given moment.8PubMed Central. Contracting actions of endothelin ET(A) and ET(B) receptors in cardiovascular disease It also influences cardiac output, how much blood the heart pumps per minute, and the capacity of veins to hold blood in reserve.9PubMed Central. Regulation of blood pressure and salt homeostasis by endothelin
Kidney Function
The kidney is both a major producer and a major target of endothelin. Within the kidney, ET-1 helps regulate blood flow to the filtering units, influences how much sodium and water get reabsorbed or excreted, and even participates in acid-base balance.10PubMed Central. Endothelin and the renal microcirculation This means that even small shifts in renal endothelin signaling can alter blood pressure indirectly by changing how much salt the body retains.
Nervous System Interactions
Endothelin is active in the brain, where it acts as a local neuromodulator involved in autonomic control of heart rate, blood pressure, and breathing. Studies in knockout mice whose ET-1 gene was disrupted showed elevated blood pressure, exaggerated sympathetic nerve activity, and impaired breathing reflexes, hinting that endothelin normally helps keep those reflexes calibrated.11PubMed. Physiological role of brain endothelin in the central autonomic control: from neuron to knockout mouse In the peripheral nervous system, ET-1 also has a sympathoexcitatory effect, meaning it nudges the sympathetic (“fight or flight”) branch toward higher baseline activity in both people with normal blood pressure and those with hypertension.12PubMed. Interactions between sympathetic nervous system and endogenous endothelin in patients with essential hypertension
Endothelin in Cardiovascular Disease
When endothelin signaling becomes chronically overactive, blood vessels tighten too much, walls thicken, and inflammation creeps in. This progression connects endothelin to several major cardiovascular conditions.
Pulmonary Arterial Hypertension
Pulmonary arterial hypertension (PAH) is a condition in which the arteries carrying blood to the lungs narrow and stiffen, forcing the right side of the heart to work progressively harder. Elevated ET-1 levels in lung tissue are a consistent finding, and endothelin appears to drive the vascular remodeling that makes those arteries thicker and less flexible over time.13PubMed. Endothelin mediates pulmonary vascular remodelling in a canine model of chronic embolic pulmonary hypertension PAH is, in fact, the disease where endothelin-blocking drugs have had their greatest clinical success so far, as discussed below.
Heart Failure and Cardiac Fibrosis
In the failing heart, ET-1 contributes to a vicious cycle. It stimulates cardiac fibroblasts to proliferate and to transform into myofibroblasts, cells that deposit excess collagen and stiffen the heart muscle. This process, cardiac fibrosis, progressively impairs the heart’s ability to fill and pump.14PubMed Central. Endothelin-1 Induces Cell Proliferation and Myofibroblast Differentiation through the ETAR/Gαq/ERK Signaling Pathway in Human Cardiac Fibroblasts In animal models, blocking endothelin receptors reduced cardiac fibrosis, shrank the thickened heart wall, and improved survival, though translating those benefits into consistent results in human heart-failure trials has been more challenging.15PubMed Central. Myocardial Fibrosis in Heart Failure: Anti-Fibrotic Therapies and the Role of Cardiovascular Magnetic Resonance in Drug Trials
Atherosclerosis
Oxidative stress, the buildup of reactive molecules that damage cells, is a well-known driver of atherosclerosis. Researchers have shown that oxidative stress ramps up ET-1 production in vascular smooth-muscle cells, creating a feedback loop: more ET-1 worsens the endothelial dysfunction that atherosclerosis thrives on, and the resulting plaque buildup generates more oxidative stress.16PubMed. Induction of endothelin-1 expression by oxidative stress in vascular smooth muscle cells
Endothelin and Kidney Disease
Beyond its normal role in the kidney, chronic overactivation of ET-1, mainly through ETA receptors, is strongly linked to kidney cell injury, protein leaking into the urine, inflammation, and the fibrosis that leads to progressive chronic kidney disease (CKD).17PubMed Central. Endothelin and endothelin antagonists in chronic kidney disease In diabetic kidney disease specifically, ET-1 promotes the scarring and stiffening of the glomeruli, the tiny filters that clean the blood.18Journal of Nephrology. Targeting endothelin signaling in podocyte injury and diabetic nephropathy-diabetic kidney disease This connection has become one of the most active areas of endothelin drug development.
Roles Beyond the Cardiovascular System
Preeclampsia
Preeclampsia, a dangerous pregnancy complication marked by high blood pressure and organ damage, involves elevated ET-1 levels in the mother’s circulation. Researchers increasingly see endothelin as a final common pathway: the placenta releases distress signals that ultimately boost ET-1 in the mother’s blood vessels, driving the hypertension and kidney dysfunction characteristic of the condition. Multiple experimental models of preeclampsia respond to ETA receptor blockade, and abnormal ETB receptor signaling may also play a role.19PubMed Central. The Endothelin System: A Critical Player in the Pathophysiology of Preeclampsia Unfortunately, existing endothelin-blocking drugs carry a risk of birth defects, which limits their use during pregnancy. Research into safer compounds or delivery methods remains active.
Systemic Sclerosis and Raynaud’s Phenomenon
Systemic sclerosis (scleroderma) is an autoimmune condition that causes widespread fibrosis of the skin and internal organs along with blood-vessel damage. Raynaud’s phenomenon, episodes in which the fingers or toes lose blood flow and turn white or blue, is one of the most debilitating vascular features of the disease. Because ET-1 is central to the vasoconstriction and fibrosis at play, several studies have evaluated endothelin receptor antagonists for treating scleroderma-related digital ulcers and Raynaud’s episodes.20PubMed Central. Endothelin Receptor Antagonists for the Treatment of Raynaud’s Phenomenon and Digital Ulcers in Systemic Sclerosis Bosentan, in particular, is used in some settings to reduce new digital ulcers in scleroderma patients.
Cancer
ET-1 has been found to promote several hallmarks of cancer progression, including cell proliferation, tissue invasion, metastasis, and the growth of new blood vessels to feed tumors (angiogenesis).21PubMed Central. Endothelin-1 and Its Role in Cancer and Potential Therapeutic Opportunities Tumors in the ovary, prostate, colon, and other sites can exploit the endothelin pathway to create a more favorable local environment. Clinical trials of endothelin receptor blockers as anti-cancer agents have produced mixed results so far, but the biology remains an active area of investigation.
Pain and Itch
ET-1 directly activates pain-sensing nerve fibers. When injected under the skin, even small amounts sensitize the area to touch, heat, and chemical irritation, while higher concentrations cause outright pain.22PubMed Central. Endothelin receptors and pain In human studies, about two-thirds of mechanosensitive pain fibers responded to ET-1, and many showed sensitization to heat that persisted for more than 15 minutes.23PubMed. Endothelin 1 activates and sensitizes human C-nociceptors Animal experiments also show that ET-1 injected into the skin provokes scratching behavior, confirming its role as an itch inducer as well.24JCI Insight. Neural peptidase endothelin-converting enzyme 1 regulates endothelin 1–induced pruritus This dual pain-and-itch signaling is thought to be relevant in conditions like sickle-cell disease and certain cancers, where elevated local ET-1 may contribute to otherwise unexplained pain.
Drugs That Block the Endothelin System
The class of drugs called endothelin receptor antagonists (ERAs) has transformed the management of PAH and is gaining ground in kidney disease. Three ERAs are widely used for PAH:
- Bosentan: a dual ETA/ETB blocker and the first ERA approved, it showed significant improvements in exercise capacity and reduced clinical worsening in PAH patients.
- Ambrisentan: a selective ETA blocker, it was the only ERA in a network meta-analysis associated with a significant reduction in the risk of patients discontinuing treatment compared with placebo, suggesting relatively good tolerability.
- Macitentan: a newer dual blocker designed for better tissue penetration, it showed the highest real-world treatment adherence in a retrospective Australian study at about 65%, compared with roughly 57–58% for bosentan and ambrisentan.25PubMed. Comparative adherence of macitentan versus ambrisentan and bosentan in Australian patients with pulmonary arterial hypertension: a retrospective real-world database study
A network meta-analysis of over 2,100 PAH patients found that all four tested ERAs improved the distance patients could walk in six minutes, and both bosentan and ambrisentan reduced the risk of clinical worsening.26PubMed Central. Endothelin-receptor antagonists in the management of pulmonary arterial hypertension: where do we stand?
In kidney disease, the most notable recent development is sparsentan, a dual-action molecule that blocks both the ETA receptor and the angiotensin II receptor in a single pill. Approved for IgA nephropathy (a common cause of kidney inflammation), sparsentan reduces protein in the urine and slows the march toward kidney failure through a mechanism that acts directly on the glomeruli.27PubMed. Sparsentan: a dual endothelin and angiotensin II receptor antagonist approved for IgA nephropathy That glomerular-level action is something older blood-pressure drugs could not achieve on their own.
Side Effects and Safety Concerns With ERAs
Blocking endothelin receptors is not without trade-offs. A meta-analysis of nearly 4,900 patients across 24 randomized trials found that, compared with placebo, ERA users had roughly double the rate of abnormal liver-function tests (about 8% versus 3%), a higher rate of peripheral edema (about 14% versus 10%), and roughly two and a half times the incidence of anemia (about 6% versus 2%).28PubMed Central. Clinical Adverse Effects of Endothelin Receptor Antagonists: Insights From the Meta-Analysis of 4894 Patients From 24 Randomized Double-Blind Placebo-Controlled Clinical Trials Liver toxicity in particular led to the withdrawal of at least one ERA (sitaxsentan) from the market and prompted mandatory liver monitoring for patients on bosentan. Dual receptor antagonists are additionally associated with salt and water retention, headache, and testicular toxicity, and all ERAs carry a warning about birth defects, making them strictly contraindicated in pregnancy.29Portal Hypertension & Cirrhosis. Endothelins and liver cirrhosis
Endothelin and Your Body Clock
One of the less appreciated features of the endothelin system is that it follows a circadian rhythm. In healthy middle-aged adults, plasma ET-1 rises through the morning hours and peaks around midday.30PubMed Central. Circadian Rhythm of Vascular Function in Midlife Adults That morning climb aligns with the well-documented spike in heart attacks and strokes during the early waking hours, and some researchers suspect that rising ET-1 levels are part of the mechanism that makes the cardiovascular system more vulnerable at that time of day.
In people with chronic kidney disease, the normal daily rhythm of ET-1 is disrupted. Their plasma ET-1 rises from midday to midnight instead of falling, and this abnormal pattern correlates with a loss of the normal nighttime dip in blood pressure, a pattern called “non-dipping” that carries extra cardiovascular risk.31PubMed. Diurnal variation in blood pressure and arterial stiffness in chronic kidney disease: the role of endothelin-1 A recent study also found that ET-1 levels were a strong diagnostic marker for distinguishing non-dipping hypertension from the dipping pattern, with a sensitivity above 80%.32PubMed. Serum endothelin-1 and endothelin-2 levels in healthy controls and circadian hypertension phenotypes: A comparison of dipper and non-dipper patients Whether correcting ET-1 levels in non-dippers could restore normal blood-pressure rhythms is an open question, but the connection underscores how tightly endothelin is woven into daily cardiovascular regulation.
An Ancient System Unique to Vertebrates
Endothelin did not evolve merely to regulate human blood pressure. Comparative genomics shows that the endothelin ligand-receptor system is a vertebrate-specific innovation, absent from invertebrates. The earliest hints of endothelin-like receptor genes appear in the cephalochordate amphioxus, a small marine animal that lacks a true backbone, but actual endothelin ligands are found only in vertebrates, from lampreys and hagfish through sharks and bony fish to mammals.33PubMed. Evolution of endothelin receptors in vertebrates
Two rounds of whole-genome duplication early in vertebrate history expanded an ancestral single endothelin gene and single receptor gene into the multi-member families we see today. An ancestral jawed vertebrate likely had four endothelin ligands and four receptors; a fourth ligand, Edn4, has been kept by bony fish but was lost in the lineage leading to land animals. Mammals also lost one of the original receptor genes, EdnrB2, from a chromosome that went on to become the mammalian sex chromosomes.34Molecular Biology and Evolution. The Endothelin System: Evolution of Vertebrate-Specific Ligand–Receptor Interactions by Three Rounds of Genome Duplication Beyond cardiovascular duties, endothelin signaling proved essential for the development of neural crest cells, the embryonic cell population that gives rise to facial bones, pigment cells, and parts of the heart and gut. That is why disrupting endothelin genes in mice causes not only blood-pressure abnormalities but also craniofacial and pigmentation defects, a reminder that the system’s reach extends far beyond blood vessels.