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Endothelial Dysfunction
Endothelial Dysfunction – The First Step Towards Coronary Disease
a report by
Paul M Vanhoutte
Head, Department of Pharmacology and Pharmacy, University of Hong Kong
More than a quarter of a century ago Robert Furchgoldltt the coronary arteries, but also inhibits the aggregation of platelets, the
demonstrated that removing the endothelial layer from the isolated expression of adhesion molecules at the surface of the endothelial
aorta of a rabbit prevents normal relaxation in response to cells and, hence, the adhesion and penetration of white blood cells
acetylcholine.
1
The ability of the endothelium to elicit relaxation was (macrophages) and the release and action of the vasoconstrictor and
soon extended to more relevant physiological stimuli (adenosine mitogenic peptide endothelin-1 (see Figure 1). The protective release of
triphosphate, bradykinin and serotonin).
2,3
The endothelial cells cause NO is exacerbated by the local presence of factors involved in the
arterial relaxation by releasing a powerful vasoactive substance(s) that coagulation of the blood, in particular the formation of thrombin and the
diffuses to the underlying layers of vascular smooth muscle and thus aggregation of platelets. If this protective role of NO fails, the stage is set
was termed endothelium-derived relaxing factor (EDRF). EDRF for the inflammatory response that will eventually lead to the formation
stimulates the activity of soluble guanylyl cyclase with the subsequent of atherosclerotic plaques.
9,16–22
production of cyclic guanosine monophosphate (cyclic GMP) in the
vascular smooth-muscle cells; it is also avidly scavenged by superoxide The protective role played by the endothelial cells against unwanted
anions.
4,5
These findings led Robert Furchgott and Louis Ignarro to the coagulation has been demonstrated repeatedly not only in vitro
3,23–26
but
proposal that EDRF is nitric oxide (NO),
6,7
a hypothesis that was proved also in vivo.
27
If constricted isolated animal or human coronary arteries
correct by Salvador Moncada.
8
Further investigations have identified with healthy endothelium are exposed to thrombin or aggregating
many components of the pathway producing NO, from the stimulation platelets, they relax immediately because of the endothelial release
of muscarinic (and other) receptors on the endothelial cells to the of NO. If the endothelium has been removed, this relaxation is no
eventual activation of an enzyme, endothelial NO synthase (eNOS or longer observed, and the aggregating platelets induce vigorous
NOS3), that transforms L-arginine into NO. When inhibitors of the constrictions as a result of their liberation of thromboxane A
2
and
enzymes involved in the pathway became available, it soon appeared serotonin (5-hydroxytryptamine). When aggregating human platelets
that NO is involved in many aspects of biology.
8
However, in the years were added to the solution, vasospasm occurred in the arteries without
that followed it also became evident that endothelial cells can affect endothelium. Thus, the healthy endothelium appears to protect blood
the tone of the underlying smooth muscle in more than one way.
9–15
vessels from vasospasm when they are threatened by aggregating
This article focuses on NO because its reduced production platelets, thrombin or the arrival of a thrombus.
characterises endothelial dysfunction, which is the first step (at least in
the author’s mind) in the long chain of events that leads to The two most important substances released by aggregating platelets
atherosclerosis and coronary disease.
9,16–19
that trigger the activation are serotonin and adenosine diphosphate
(ADP). The former is dominant and stimulates 5-HT
1D
serotonergic
The Protective Role of the Endothelium receptors of the endothelial cell membrane. ADP is a relatively minor
The release of NO plays an essential role in the protection exerted by the contributor that acts on P
2y
purinergic receptors. These two products
endothelial cells against coronary disease. Indeed, the endothelial trigger distinct signalling cascades in the endothelial cells (see Figure
mediator not only prevents abnormal constrictions (vasospasm) of 1). The stimulation of serotonergic receptors (and of those for
thrombin) is coupled to the activation of eNOS through pertussis
toxin-sensitive Gi-proteins, and purinergic receptors follow a Gq-
Paul M Vanhoutte is Head of the Department of
Pharmacology and Pharmacy at the University of Hong
dependent cascade.
25-29
Kong, where he is also Director of the BioPharmaceutical
Development Centre. He is an Honorary Professor at the
If platelet aggregation were to occur in a coronary artery with a normal
Peking Union Medical College (Beijing), the Institute of
Materia Medica of Beijing, the Ocean University of Qingdao,
endothelium, the release of serotonin (and ADP) and the local initiation
the Second Military Medical University in Shanghai and the
of the coagulation cascade (with the production of thrombin) would
Shanghai Institute of Materia Medica. Dr Vanhoutte is a
become a strong signal for the endothelial cells to release NO. The
member of the Academia Europea and the Belgian Academy
of Medicine and an honorary member of the Brazilian Academy of Medicine. His major endothelial mediator will not only cause the underlying smooth-muscle
scientific contribution has been to appreciate and analyse the importance of endothelial cells
cells to relax, allowing the beginning aggregate to be flushed away by the
in the control of the underlying vascular smooth muscle in health and disease. Dr Vanhoutte
received a Doctor Honoris Causa degree from the University of Gent in 2001, from the
flow of blood, but will also exert, hand in hand with prostacyclin, which
Universities of Antwerp, Montreal and Zurich in 2003, from the Royal Melbourne Institute of is also released, an immediate feedback inhibition of the platelet
Technology in 2005 and from the University Louis Pasteur in Strasbourg in 2006.
aggregation process. Under normal conditions, if the endothelial barrier
E: vanhoutt@hku.hk
is interrupted by injury, the aggregating platelets can move to the
immediate vicinity of the vascular smooth-muscle cells. The thromboxane
64 © TOUCH BRIEFINGS 2008
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