The Discovery of Endothelin

Overview

Endothelin refers to a family of three 21-amino-acid peptides (ET-1, ET-2, ET-3) first identified in 1988 by Masashi Yanagisawa and colleagues at the University of Tsukuba. Working with media conditioned by cultured porcine aortic endothelial cells, they purified a peptide with extraordinarily potent and long-lasting vasoconstrictor activity. ET-1 proved to be one of the most potent vasoconstrictors known, active at picomolar concentrations.

Endothelins are produced from larger preproendothelin precursors, processed first to "big endothelin" and then cleaved by endothelin-converting enzyme (ECE) to the mature 21-amino-acid peptide. They act through two G protein-coupled receptors, ETA and ETB, with distinct tissue distributions and physiological effects. ETA is mainly on vascular smooth muscle and mediates vasoconstriction and mitogenesis; ETB is expressed on endothelial cells and vascular smooth muscle and has more complex effects including nitric oxide release and endothelin clearance.

The discovery reshaped vascular biology. It revealed that the endothelium, long considered a passive barrier, produces its own vasoactive peptides, complementing the vasodilator nitric oxide discovered around the same time by Robert Furchgott, Louis Ignarro, and Ferid Murad.

Key People

• Masashi Yanagisawa: Japanese physician-scientist who led the 1988 endothelin discovery as a graduate student.
• Tomoh Masaki: Senior author who supported and co-led the Tsukuba research program.
• Robert Furchgott, Louis Ignarro, Ferid Murad: 1998 Nobel laureates for nitric oxide research that paralleled endothelin work.
• Hossein Ardeschir Ghofrani, Lewis Rubin: Contributors to clinical pulmonary arterial hypertension research.

Timeline

• 1985–1987: Observations of endothelium-derived vasoconstrictor activity in cultured endothelial cell supernatants.
• 1988: Yanagisawa et al. publish the endothelin structure and sequence.
• 1989: ET-2 and ET-3 identified.
• 1990: ETA and ETB receptors are cloned.
• 2001: Bosentan, a dual ETA/ETB antagonist, is approved for pulmonary arterial hypertension.
• 2007: Ambrisentan, a selective ETA antagonist, is approved.
• 2013: Macitentan, a tissue-targeted dual antagonist, is approved.

Background

Endothelin research emerged in parallel with the rise of modern vascular biology. Where earlier vasoactive peptides such as angiotensin and bradykinin were known to circulate systemically, endothelin was novel in being produced and acting largely locally at the level of the vascular wall. This autocrine-paracrine model of vascular regulation reframed how researchers thought about blood pressure, organ perfusion, and vascular disease.

The endothelin system is now implicated in pulmonary hypertension, systemic hypertension, heart failure, atherosclerosis, kidney disease, and cancer. Excess endothelin signaling contributes to vasoconstriction, proliferation, and fibrosis. In certain disease states, such as scleroderma-associated pulmonary arterial hypertension, endothelin receptor antagonists can significantly improve hemodynamics and functional capacity.

Modern Relevance

Endothelin receptor antagonists (ERAs) are established therapy for pulmonary arterial hypertension, where they reduce pulmonary vascular resistance and improve exercise capacity. They are also under active investigation for resistant hypertension, diabetic kidney disease, chronic kidney disease with proteinuria, and certain malignancies. In 2023, aprocitentan was approved for resistant hypertension, extending the class into broader cardiovascular use.

Research on endothelin continues to explore tissue-specific roles (e.g., in the brain, reproductive tract, and skin), interactions with the renin-angiotensin and natriuretic peptide systems, and potential biomarker applications. For related vasoactive peptides, see atrial-natriuretic-peptide-history and angiotensin-history.

Related Compounds

• Endothelin-1
• Bosentan
• Ambrisentan
• Macitentan
• Aprocitentan