Endothelin: Still Beyond Reach
That endothelin can be boon or bane, and that it plays a role in so many functions in so many species, are what make it so intriguing. Because the protein is the same in different animals, experiments in mice and rats, for example, should be particularly useful in predicting how a disease may progress in humans—or how a new drug might arrest its development. But even more important is that one or a few therapies could have widespread effects in regulating endothelin and therefore treating the many diseases in which it is involved.
That’s why, after endothelin was discovered in 1988, in the blood vessels of pigs, scientists became giddy with excitement about all they might do with the protein. Drugs to block ET could be used to lower blood pressure, to treat chronic kidney disease and perhaps even to cure cancer—or so they thought. Yet after more than 20 years of research, few of those ideas have come to fruition. Only two rare diseases have approved treatments resulting from ET research, and those therapies can have serious side effects. But the work continues, and with more than 25 clinical trials currently under way, the once-ebullient endothelin researchers are cautiously hopeful that their favorite protein will yet live up to their ambitious dreams.
Endothelin took its name from the place the protein was discovered—in the endothelium of blood vessels—though it might just as easily have been found almost anywhere in the body. The endothelium is a single layer of cells that lines the walls of blood vessels, and scientists had long believed those cells just provided passive physical protection to the vessels. But in 1980, Robert Furchgott, a scientist at the State University of New York’s Downstate Medical Center in Brooklyn, noticed that endothelial cells release a substance that causes blood vessels to widen, thus reducing the pressure inside them. In 1987 that substance was identified as nitric oxide,and Furchgott shared the 1998 Nobel Prize in Physiology or Medicine for his discovery and subsequent work on the gas.
Meanwhile, in 1985 Robert Highsmith and his colleagues at the University of Cincinnati College of Medicine found that endothelial cells also release another substance, one that appeared to counterbalance the dilation caused by nitric oxide. Highsmith placed endothelial cells in a liquid medium and applied the medium to a specimen of pig coronary artery. The cells contracted.
It took three years for researchers to identify the protein triggering this constriction. In Tsukuba, Japan, graduate student Masashi Yanagisawa came across Highsmith’s paper about his team’s work and proposed, for his doctoral thesis, to identify the mystery substance. His supervisor, Tomoh Masaki, and several other researchers joined the quest, and in March 1988, in the journal Nature, Yanagisawa published a paper that launched an entire field of research. The paper described the protein—a 21-amino-acid peptide—and the DNA sequence that encodes it, and named it endothelin. The team’s experiments had established that endothelin was by far the most powerful vasoconstrictor ever encountered, 10 times as potent as the previous record holder, a protein called angiotensin II.
Researchers next figured out where the endothelin goes after being released by endothelial cells: It binds to ET receptors on the membranes of the blood vessel’s smooth muscle cells, clearing the way for calcium to be released into them, which causes them to contract, shrinking the diameter of the vessel. That effect is counterbalanced by other factors (including, in some cases, ET itself) that help the vessel dilate. This tension between shrinking and expanding maintains vascular tone, keeping blood vessels from collapsing in on themselves.