CARDIOVASCULAR JOURNAL OF AFRICA • Vol 23, No 4, May 2012
AFRICA
223
initiate vasodilation in response to vasodilatory stimuli such as
acetylcholine or shear stress. It represents an initial reversible
step in the development of atherogenesis, and for this reason,
early clinical identification of ED may become an important tool
in the prevention or reversal of progression to atherosclerosis
and IHD.
7
ED comprises a loss of balance between endothelial-
derived vasodilatory and vasoconstrictory factors, where
the pro-vasoconstrictory state becomes dominant, leading to
progressive pathophysiological changes. These changes appear
as sequentially occurring responses in endothelial cells, also
referred to by some as the endothelial activation–dysfunction–
injury triad.
8,9
Collectively, these endothelial changes exhibit
pro-inflammatory, pro-oxidant, proliferative, pro-coagulation
and pro-vascular adhesion features.
7,10
The endothelium: a functional organ
The vascular endothelium consists of approximately 1–6
×
10
13
endothelial cells and accounts for about 1 kg of total body weight.
For many years after its discovery, the endothelium was believed
to be an inert, semi-permeable barrier between circulating
blood and the underlying sub-endothelial tissues.
11
However,
extensive research has since revealed a far more complex role
for the endothelium. We now know that the endothelium is in
fact a metabolically active organ, playing a crucial role in the
maintenance of vascular homeostasis by releasing a variety of
vasoactive factors that can either dilate or constrict the blood
vessels, depending on the type of the stimulus.
7
Vascular homeostasis entails keeping a tightly controlled
balance between a vasodilatory state, which is often associated
with anti-oxidant, anti-inflammatory and anti-thrombotic effects
on one hand, and a vasoconstrictory state on the other, which is
associatedwithpro-oxidant,pro-inflammatoryandpro-thrombotic
effects.
12
The vasodilatory state is mediated by factors such as
nitric oxide (NO), endothelium-derived hyperpolarising factor
(EDHF) and prostacyclins, while a vasoconstrictory state is
mediated by factors such as endothelin-1 (ET-1), angiotensin
II and thromboxane A2.
7,12
Of these endothelial-derived factors,
NO, which was originally identified as the endothelial-derived
relaxing factor (EDRF), has since evoked much interest as it
is considered to be the most potent endogenously synthesised
vasodilator in the body, and a key marker of endothelial function
and dysfunction.
The vasoactive factors released by endothelial cells and their
effects are summarised in Table 1. In view of the physiological,
pathophysiological and clinical importance of NO in vascular
physiology, we have included a brief discussion on the physiology
of NO below.
Nitric oxide
The realisation in the 1980s that the identity of EDRF was in fact
NO was rather astonishing, as NO had until then been perceived
as nothing more than a toxic environmental pollutant found
in cigarette smoke, exhaust fumes of motor cars and harmful
gases generated by industrial processes.
13,14
The ground-breaking
discovery that NO is also synthesised in the body and functions
as a chemical messenger with important physiological effects
introduced a novel paradigm in cardiovascular physiology and
pathophysiology. In addition to its vasodilatory properties, NO
was also found to exert anti-inflammatory and cardioprotective
effects.
15
Owing to its gaseous and free-radical nature, NO is able
to diffuse easily between cells and tissues and react with a
variety of molecules in the body.
13
NO is synthesised from
the amino acid L-arginine by a family of enzymes known as
nitric oxide synthase (NOS).
14
The NOS enzyme occurs as
TABLE 1. OVERVIEW OF ENDOTHELIUM-DERIVEDVASO-ACTIVE FACTORS
Endothelium-derived factors Physiological effects
Enzymatic source and mechanism of action
Nitric oxide (NO)
• Potent vasodilator
• Inhibits inflammation, VSMC proliferation and migra-
tion, platelet aggregation and adhesion, and leukocyte
adhesion
• Regulates myocardial contractility
• Regulates cardiac metabolism
• Cardioprotective during ischaemia–reperfusion injury
• Synthesised by the enzymes: eNOS, nNOS and iNOS,
with eNOS the major endothelial source of NO during
physiological conditions
• Diffuses from endothelial cells to underlying VSMCs
where it binds to soluble guanylyl cyclase, leading to
a cascade of events that ultimately result in vascular
relaxation
Prostacyclin (PGI
2
)
• Vasodilatory agent
• Inhibits platelet aggregation
• Derived from arachidonic acid by cyclooxygenase-2
(COX-2)
Endothelium-derived
hyperpolarising factor
(EDHF)
• Exerts vasodilatory effects, particularly in small arter-
ies of diameter
≤
300
μ
m
• Its identity is still under suspicion with proposed
candidates such as potassium ions and hydrogen
peroxide
• Causes relation of VSMCs by means of membrane
hyperpolarisation
Endothelin-1 (ET-1)
• A potent vasoconstrictor
• Synthesised by endothelin-converting enzyme
• Exerts its effects via two receptors: ET
A
expressed
on endothelial cells and ET
B
on VSMCs. ET
A
recep-
tors promote vasoconstriction, whereas ET
B
receptors
promote NO production and ultimately reduction in
ET-1 production
Thromboxane A (TXA
2
)
• A potent vasoconstrictor
• Derived from arachidonic acid by COX-1
Angiotensin ll
• A potent vasoconstrictor
• Synthesised by angiotensin converting enzyme
• Elicits its effects via two receptors: AT
1
which
promotes vasoconstriction and cell proliferation, and
AT
2
which antagonises the effects of AT
1
