59 / 64
AFRICA
S57
CVJAFRICA • Volume 26, No 2, H3Africa Supplement, March/April 2015
The endothelium
Robert FFurchgott, Louis J Ignarro and FeridMurad catalysed the
wave of research that improved our understanding of endothelial
function, which led to the joint award of the 1998 Nobel Prize
in Physiology or Medicine ‘for their discoveries concerning nitric
oxide as a signaling molecule in the cardiovascular system’. We
now recognise that the healthy endothelium is in a quiescent state
where nitric oxide (NO) produced by the endothelial isoform of
nitric oxide synthase (eNOS) in its membrane-bound configuration
is released, to silence cellular processes, by targeting cysteine groups
in regulator molecules such as NF
κ
B and the mitochondria.
8
On the other hand, endothelial dysfunction is an activated state
where the regulatory proteins such as NF
κ
B and phosphatases
are targeted by reactive oxygen species (ROS) produced from
oxidases and eNOS uncoupling. Endothelial activation can occur
physiologically in response to immune system perturbation, as
well as pathophysiologically secondary to cardiovascular risk
factors. Persistent ROS signalling precipitates a loss of vascular
integrity characterised by detachment of endothelial cells and
dependence on circulating progenitor cells for repair due to
limited capacity of contiguous endothelial cells.
8
The relationship between risk-factor profile, endothelial
dysfunction and circulating endothelial progenitor cells has
been evaluated using flow-mediated dilatation (FMD) of the
brachial artery. In their report, Hill and colleagues demonstrated
that the presence of high levels of endothelial progenitor cells
preserves endothelial function despite significant risk-factor
burden.
9
Similarly, the relationships between FMD and coronary
disease risk factors in asymptomatic adults,
10
diet and exercise
in overweight teenagers,
11
and glucose and other metabolic
syndrome components have been reported.
12
Beyond the association with cardiovascular risk factors, other
measures of endothelial function have been associated with
cardiovascular disease outcomes. Greater event-free survival
has been associated with intracoronary acetylcholine-induced
vasodilatation in coronary angiography patients,
13
increased
brachial artery reactivity indexed by FMD in vascular surgery
patients,
14
and increased baseline levels of endothelial progenitor
cells in CAD patients.
15
Furthermore, there is evidence to
indicate early risk-factor exposure and endothelial dysfunction
impact on the development of atherosclerosis and subsequent
cardiovascular outcomes.
16,17
Thepromotionof endothelialhealthandreversalof endothelial
dysfunction have been associated with increased physical activity,
consumption of diets rich in fruit and vegetables, and avoidance
of tobacco use or exposure to tobacco smoke.
18-24
Consequently,
the endothelium has remarkable relevance in clinical and public
health practise as well as in health education, health promotion
and prevention strategies, and therefore has implications for
the epidemiological transition unfolding in developing world
regions such as sub-Saharan Africa. In addition, it suggests that
additional research into endothelial function, activation and
dysfunction could provide novel proximal targets for clinical,
public health and public policy interventions, in an effort to
achieve maximum impact on population health.
Public health relevance
The structure of the endothelium constitutes a remarkable
feature, given its complexity, vast spatial distribution, and
heterogeneity in different vascular beds. Combined with its role
in the control of vasomotor tone, inflammation, homeostasis,
endocrine and paracrine regulation, and cell growth, trafficking
and survival,
25
the endothelium has remarkable implications
for CVD and other NCDs such as cancer, diabetes and chronic
lung disease. Therefore, it is not surprising that endothelial
biomedicine is recognised as a transdisciplinary field.
Population research evidence indicates that social determinants
and drivers such as globalisation, urbanisation, ageing, income,
education and housing are all linked with stress levels associated
with CVD and other diseases, and connected with behavioral
risk factors – unhealthy diet, tobacco use, physical inactivity and
harmful use of alcohol, which are associated with metabolic risk
factors such as high blood pressure, obesity, diabetes and raised
blood lipid levels that ultimately lead to the manifestations of
various diseases.
In a recent study of cardiovascular risk and events in 17 low-,
middle- and high-income countries, it was noted that compared
to high-income country populations, the risk factors for CVD
were lower in low-income country populations, but disease
outcomes were substantially worse, which potentially suggests
both poor delivery of effective clinical care and higher stress
levels in low-income country populations.
26
The endothelium provides a construct for understanding
how these networks of social, behavioural and metabolic factors
converge to cause a network of diseases. The socio-behavioral
and biological drivers lead to pathophysiological activation of
the endothelium, resulting in a favourable bio-molecular milieu,
for example inflammation and atherosclerosis, for disease in
various vascular beds and organ systems due to the expansive
spatial distribution of the endothelium (Fig. 1).
Therefore the endothelium provides a target for cross-cutting
disease strategies given the broad implications of its dysfunction.
Since moderate levels of physical activity on most days of the
week, diets rich in fruit and vegetables and low in saturated and
trans fats, and tobacco avoidance have been shown to improve
endothelial health and reverse endothelial dysfunction, the
adherence to public health strategies for improving physical
activity and nutrition are essential for health promotion and
the prevention of CVD, which aligns with clinical guideline-
recommended interventions for the treatment and control of the
common risk factors associated with CVD.
However, we need to move beyond current approaches by
deliberately seeking transformative ways to achieve further
substantial decline in CVD morbidity and mortality rates.
Here, it is important to build on the wealth of scientific
information on the endothelium, which has not been tapped
by public health practitioners and researchers for translation
into policies, programmes and research initiatives for advancing
cardiovascular health promotion and the prevention of CVD.
Challenges and opportunities
Although the endothelium establishes dialogue with every tissue
cell in the body, is affected by many disease processes and
risk factors, and contributes to the initiation and progression
of chronic diseases, it remains underappreciated until it is
dysfunctional. Furthermore, although measures to improve or
preserve endothelial health are relatively inexpensive, they are often
less supported than more expensive disease-intervention strategies.