Paracrine Control of Blood Vessel Function 
Role of the Endothelins 
Masasbi Yanagisawa, M.D., Ph.D. — Associate Investigator 
Dr. Yanagisawa is also Associate Professor of Molecular Genetics at the University of Texas Southwestern 
Medical Center at Dallas. He received his M.D. and Ph.D. degrees from the University of Tsukuba, Japan, 
where he worked with Tomoh Masaki. Before moving to Dallas, he was Assistant Professor of 
Pharmacology at Kyoto University, Japan. 
DISORDERS of blood vessels, including all 
forms of heart attack and stroke, represent 
the most frequent disease cause of death in devel- 
oped countries. The inner surface of blood vessel 
walls is lined with a thin monolayer of flat cells 
called vascular endothelium. These cells cover a 
total surface area of nearly 700 m^ throughout 
the human body. The endothelium is also unique 
in that it is the only tissue that has direct physical 
contact with circulating blood under healthy 
conditions. Nevertheless, until a little over 10 
years ago, the endothelial cells were considered 
to be merely a "bio-inert dialysis bag." In other 
words, they just kept blood flowing smoothly 
without unwanted clotting and allowed nutri- 
tional components and metabolites to pass freely 
between the blood and interstitial space. 
Evidence accumulated recently, however, indi- 
cates that the endothelium plays much more 
complex roles in many different facets of physiol- 
ogy and pathology. The endothelial cells can re- 
spond to both chemical (circulating and local 
hormones) and mechanical (local blood flow and 
pressure) information carried in the circulating 
blood. 
In response to these stimuli, these cells trigger 
remodeling and de novo formation of blood ves- 
sels by secreting growth factors and migrating 
into adjacent tissues. They also regulate leuko- 
cyte infiltration and lymphocyte homing by ex- 
pressing a variety of cell adhesion molecules. 
They integrate blood coagulation, fibrinolysis, 
and platelet function by producing various pro- 
and anticoagulant factors. They control vascular 
permeability by actively transcytosing and metab- 
olizing plasma components. Finally, they regu- 
late blood pressure and local blood flow by both 
activating and inactivating circulating vasoactive 
factors and, more importantly, by generating an 
array of vasoactive molecules. Thus we now rec- 
ognize the vascular endothelium as an active and 
dynamic transducer that senses and interprets 
blood-borne signals. 
Central to these functions of the endothelium 
is local communication of the endothelial cells 
with vascular smooth muscle cells underneath. 
As mentioned above, the endothelial cells send 
out an array of physiological and pathological 
signals toward the smooth muscle cells by means 
of the endothelium-derived vasoactive factors. 
Among those are prostacyclin and nitric oxide 
(also called endothelin-derived relaxing factor), 
both strong vasodilators. 
This background led us in 1988 to identify en- 
dothelin-1 (ET-1), a novel vasoconstrictor pro- 
duced by vascular endothelial cells. ET-1 is a 
small peptide consisting of 21 amino acid resi- 
dues wound into a rigid structure by two sets of 
intrachain disulfide bridges. It is the most potent 
vasoactive molecule known, causing a strong and 
extremely sustained constriction of all blood ves- 
sels both in vitro and in vivo. 
Our subsequent studies demonstrated in hu- 
mans and other mammals three endothelin- 
related genes that encode, besides ET-1, two ad- 
ditional isopeptides of the endothelin family 
called ET-2 and -3. Endothelin isopeptides are 
expressed with distinct distribution patterns in 
many mammalian tissues. While the endothelial 
cells are the most abundant source of ET- 1 , one or 
more of the three isopeptides are expressed 
widely in other tissues such as brain, lung, and 
kidney. 
The production of endothelins is regulated in 
both directions. In endothelial cells, it is up- 
regulated by various chemical stimuli, including 
classical vasoactive hormones (epinephrine, an- 
giotensin II, and vasopressin) , products from co- 
agulation/platelet activation (thrombin and 
transforming growth factor-jS) , factors implicated 
in septic shock (bacterial endotoxin, interleukin- 
1, and tumor necrosis factor), oxidized low- 
density lipoprotein, etc. ET-1 production is also 
augmented by mechanical stimuli such as stretch 
and fluid-dynamical shear stress. In contrast, cer- 
tain vasodilators (nitric oxide and atrial natri- 
uretic peptides) attenuate the ET-1 production 
via increase of intracellular cGMP levels. 
Like many other peptide hormones and neuro- 
peptides, endothelins are processed from the 
corresponding larger precursor proteins (pre- 
pro-proteins). However, biologically active 21- 
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