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The Strongest Vessel Constrictor Ever Found Is a Peptide: Endothelin and Its Snake Venom Twin
For years, scientists suspected that the cells lining blood vessels release something that makes the vessel wall tighten. Nobody could catch it. In 1988, a young researcher in Japan finally did, and the molecule turned out to be a peptide with a surprising relative hidden in the venom of a desert snake.
Key takeaways
- Masashi Yanagisawa and colleagues at the University of Tsukuba isolated endothelin from cultured pig blood vessel cells in 1988.
- It is a peptide of 21 amino acids with two disulfide bonds.
- It is among the most potent vessel-constricting substances known.
- A group of venom peptides from a burrowing snake, called sarafotoxins, has almost the same sequence.
- Endothelin comes from a larger precursor that is cut by an enzyme to its active form.
A suspected factor
In the early 1980s researchers learned that blood vessels respond differently when the inner lining, the endothelium, is present or removed. One discovery showed that the lining releases a relaxing factor, later identified as nitric oxide. Other experiments hinted that the lining also releases a constricting factor, but it could not be isolated.
The catch
Yanagisawa worked in the laboratory of Tomoh Masaki. They grew pig endothelial cells in culture and tested the liquid around them on strips of pig artery. The medium made the arteries contract slowly and powerfully. By purifying the medium step by step, they found the active molecule and worked out its sequence. It was a peptide of 21 amino acids held in a compact shape by two disulfide bonds, which they named endothelin. The paper was published in Nature in 1988.
The snake connection
Almost at once, researchers noticed that endothelin looks very much like a group of toxins in the venom of an Israeli burrowing snake, Atractaspis engaddensis. The venom peptides, called sarafotoxins, are about the same length, have the same disulfide pattern and differ only slightly in sequence. Sarafotoxin can cause the heart arteries to constrict so severely that the animal dies. It is a striking example of a toxin that mimics a natural signal, much like the cone snail peptides in our cone snail story.
Made in two steps
Cloning the gene showed that endothelin is made as a much larger precursor. An enzyme then clips it to the active 21-amino-acid form. This is common for peptide hormones, and the same logic of precursor processing applies to many peptides. Studying it requires reliable ways to separate precursor from product, which is why mass spectrometry, as in our MS/MS post, is so useful.
Why it mattered
Endothelin turned out to act through two receptors and to play roles in vessel tone, development and disease models. Small molecules that block the endothelin receptor were developed and approved in the 2000s. Yanagisawa, who later co-discovered orexin, became one of the best-known peptide discoverers of his generation, as told in our orexin story.
Lab angles
- Cell culture medium can be a source of unknown peptides if you fractionate it carefully.
- Two disulfides need correct pairing, so cysteine handling matters.
- Bioassays on isolated tissue, such as vessel assays, are still used.
- Binding and function are separate questions, as in radioligand binding.
The bottom line
Endothelin shows how a small peptide can control a major physiological property, and how nature reuses a design in a venom. For more peptide discovery stories, browse the Research Library.
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For laboratory research use only. Not for human or veterinary use, and not intended to diagnose, treat, cure or prevent any condition. This article is educational and is not medical advice.