The Open Cardiovascular Medicine Journal, 2010, 4, 89-96 89
1874-1924/10 2010 Bentham Open
Vascular Function and Inflammation in Rheumatoid Arthritis: the Role of
George S. Metsios1,2,*, Antonios Stavropoulos-Kalinoglou1,2, Aamer Sandoo2, Jet J.C.S. Veldhuijzen
van Zanten2, Tracey E. Toms2, Holly John2 and George D. Kitas2
1School of Sport Performing Arts and Leisure, University of Wolverhampton, Walsall, West Midlands, United Kingdom
2Department of Rheumatology, Dudley Group of Hospitals NHS, Foundation Trust, Russell’s Hall Hospital, Dudley,
West Midlands, United Kingdom
Abstract: Inflammation disturbs biochemical pathways involved in homeostasis of the endothelium. Research has estab-
lished clear links between inflammatory mediators, particularly C-reactive protein and tumour necrosis factor alpha,
endothelial dysfunction, and atherosclerosis. Endothelial dysfunction and atherosclerosis may be subclinical at early
stages, and thus the ability to detect them with non-invasive techniques is crucially important, particularly in populations
at increased risk for cardiovascular disease, such as those with rheumatoid arthritis. This may allow the identification of
interventions that may reverse these processes early on. One of the best non-pharmacological interventions that may
achieve this is physical activity. This review explores the associations between inflammation, endothelial dysfunction,
and atherosclerosis and discusses the role of exercise in blocking specific pathways in the inflammation, endothelial dys-
function - atherosclerosis network.
Keywords: Inflammation, Atherosclerosis, Endothelial function, Cytokines, Vascular function, Exercise, Physical activity,
lining the entire vascular system. It is responsible for many
atheroprotective functions via its regulation of the immune
response, fibrinolysis, coagulation, as well as multiple other
functions related to vascular growth, vasoprotection, and
vasoregulation. Disruption of normal endothelial function
impedes its protective effects on vascular homeostasis, an
early event characterizing the development of cardiovascular
disease (CVD) [1-3]. Most importantly, endothelial dysfunc-
tion and the early stages of CVD may occur in the absence of
any clinical symptoms. Hence, finding methods for assessing
vascular dysfunction during the early stages of the disease is
important, particularly in patient groups at high CVD risk
The endothelium is now regarded as a dynamic organ
inflammatory arthritis characterized by symptoms and signs
of joint and systemic inflammation, joint destruction, body
composition alterations, and physical disability. It also asso-
ciates with high CVD morbidity and mortality, which are
not fully explained by the presence of traditional CVD risk
factors [5-8]. In RA, increased local (synovial) and systemic
expression of specific inflammatory mediators may have
detrimental effects on the endothelium by enhancing bio-
chemical processes leading to its dysfunction and eventually
*Address correspondence to this author at the School of Sport Performing
Arts and Leisure, University of Wolverhampton, Wolverhampton, West
Midlands, United Kingdom; Tel: +44-0121-4561302;
Rheumatoid arthritis (RA) is the most common chronic
the development of atherosclerosis [2, 9]. Indeed, the
inflammatory pathways involved in the pathogenesis of RA
and atherosclerosis share many characteristics . Inflam-
mation in RA is often evaluated by measuring the acute
phase reactant C-reactive protein (CRP) and/or the erythro-
cyte sedimentation rate (ESR), which, in combination with
other clinical markers (e.g. disease activity or X-ray scores),
are used to assess the disease state and response to treatment
. The acute phase response is attributed to increased lev-
els of pro-inflammatory cytokines, such as tumour necrosis
factor alpha (TNF-alpha) and interleukin-6 (IL-6) ,
which are individually or synergistically involved in many
other disease processes, including joint destruction 
altered body composition , and changes in vascular
homeostasis [14, 15].
INFLAMMATION AND ENDOTHELIAL DYSFUNC-
vasoactive factors such as nitric oxide (NO), prostacyclin
(PGI2), and endothelin-1 (ET-1). Endothelial dysfunction
occurs when the balance between these vasoactive factors is
disturbed. The down-regulation of endothelial NO synthase
(eNOS) plays an important role in this process . Altered
endothelial homeostasis due to the disturbed NO production is
characterized by diminished endothelium-dependent dilation
and increased expression of adhesion molecules, as well as
changes in endothelial cell phenotype and increased endothe-
lial permeability . Such changes in the structure and
function of the endothelium are thought to be important as
The endothelium controls vascular function by releasing
90 The Open Cardiovascular Medicine Journal, 2010, Volume 4 Metsios et al.
initial stages in the pathogenesis of atherosclerosis and CVD
inflammation and endothelial dysfunction. In vitro, CRP
modulates eNOS activity of human endothelial cells [19, 20]
via uncoupling eNOS and subsequently increasing superox-
ide anions (oxidative stress) from NADPH oxidase . As
a result, phosphorylation of eNOS is decreased, and this
subsequently reduces bioavailability of NO . Apart from
NO, CRP upregulates the expression of ET-1 which is a
vasoconstrictor . Studies also reveal a direct effect of
TNF-alpha on dowregulating the expression of eNOS and
diminishing endothelial NO . TNF-alpha downregulates
at the same time enzymatic activities of eNOS and
argininosuccinate synthetase (regulator of citrulline/NO
cycle)  and induces an increase in mRNA degradation of
both eNOS and neuronal NO synthase promoting vasocon-
striction . In addition, by activating NADPH oxidase,
TNF-alpha stimulates the generation of reactive oxygen spe-
cies within the endothelial environment further impairing
NO-mediated vasodilation . Apart from inhibition of NO
production, TNF-alpha may also be responsible for the re-
duction in the bioavailability of NO . This is perhaps the
main reason why TNF-alpha inhibition is directly linked to
improved endothelial function in both RA  and non-RA
Several studies have established a strong link between
significantly worse in RA compared to healthy controls and
this is attributed in large part to the high-grade inflammatory
state of RA [30, 31]; in fact, acute inflammation (e.g. in re-
sponse to immunization) and low-grade chronic systemic
inflammation (detected using high sensitivity CRP assays) in
healthy individuals has been directly linked with arterial
stiffness and vascular dysfunction [32, 33]. However, despite
this biologically plausible link between inflammation and
vascular dysfunction, there are still some controversies
and inconsistent results in RA [34, 35], where some studies
report a lack of association between systemic inflammatory
load and endothelial function [36-38]. This may be attributed
to different methodological approaches (e.g. using small,
diverse patient populations cross-sectionally, or even smaller
populations longitudinally but with short time courses), or
lack of sufficient statistical power and no correction for mul-
tiple potential confounders (e.g. age and many CVD risk
factors). The link between inflammation and vascular func-
tion appears to be more consistently demonstrated in homo-
geneous RA samples, such as young patients, patients with
new onset RA and without established CVD [31, 39]. Vascu-
lar function may progressively deteriorate during the course
of RA . Hence, RA patients with long disease duration
may already have significantly impaired endothelial function
at the time of assessment, irrespective of disease “current”
activity. Given the fluctuations in inflammation characteris-
tic of RA, it might be that longstanding, though intermittent,
inflammatory insult to the endothelium is of more impor-
tance to vascular function in RA than the current level of
inflammation . Studies that took into account long-term
inflammatory burden have been able to demonstrate associa-
tions between this and vascular function [36, 39].
Endothelial function and morphology are reported to be
INFLAMMATION AND ATHEROSCLEROSIS
appears to be amongst the earliest processes involved in
atherosclerosis. Reduction of NO bioavailability disrupts the
balance of the vasoactive factors, which allow ET-1 levels to
increase and cause vasoconstriction . Along with the
biochemical mediators of endothelial function, mechanical
forces and in particular, shear stress are also responsible for
altering the phenotype of endothelial cells. Shear stress is the
tangential stress that is applied to the artery wall and induces
distension of the arteries; it is long-known that atheroscle-
rotic lesions originate mainly in areas of low shear stress,
where flow is disturbed [42, 43]. In these areas, endothelial
cells promote a pro-atherogenic phenotype , enhancing
both the local selectivity of plaque formation, as well as ves-
sel wall remodeling, which, in turn, affects plaque vulner-
Endothelial cell dysfunction, evident as NO deficiency,
ticularly monocytes, progressively transmigrate through the
endothelium with the help of monocyte chemoattractant pro-
tein 1 (MCP-1) and IL-8 . Atherosclerosis progresses via
the differentiation of monocytes into macrophages that retain
low-density lipoproteins and become foam cells. Increased
permeability of RA endothelial cells further enhances the
entry of low-density lipoproteins and further promotes this
cascade of events . It has now been well-established that
inflammation is involved in all phases of the atherothrom-
botic processes . Whereas MCP-1 and IL-8 regulate
monocyte transmigration, IL-8 can be upregulated in endo-
thelial cells by CRP via the NF-kB pathway . CRP can
also increase the expression of macrophage colony stimulat-
ing factor (M-CSF), responsible for the differentiation of
monocytes into macrophages. Subsequently, macrophage
proliferation increases, thereby enhancing the progression of
atherosclerosis via the promotion of the formation of foam
cells . An alternative effect of CRP is to destabilize the
atheromatous plaque at later stages of atherosclerosis, by
upregulation of matrix metalloproteinases  which causes
weakening of the plaque’s, fibrous cap. Apart from the
above effects of CRP on these individual steps of atheroscle-
rosis, it also enhances fibrinolytic procedures within the en-
dothelial environment. CRP increases plasminogen activator
inhibitor-1 mRNA through induction of the NF-kB signal-
ling pathway  and downregulates endothelial tissue
plasminogen activator, a serine protease that is responsible
for fibrinolysis. This biochemical process is orchestrated by
TNF-alpha and IL-1b . Other important atherogenic
properties of CRP include CRP-induced oxidative stress via
overproduction of reactive oxygen species . Reactive
oxygen species in the endothelium enhance degradation of
eNOS via eNOS uncoupling and subsequent increase in su-
peroxide . In general, superoxide reacts rapidly with NO,
forming peroxynitrite which significantly impairs NO bioac-
tivity  and deteriorates endothelial function.
At the initial stages of atherosclerosis, leukocytes, par-
by altering the distribution of endothelial cadherin-catenin
and inhibiting the re-structure of F-actin fibers . This
procedure may enable monocyte transmigration into the en-
dothelium and amplify the cascade of procedures that favor
the formation of foam cells from macrophages . Fur-
TNF-alpha has direct effects on endothelial permeability
Vascular Function and Inflammation in Rheumatoid Arthritis The Open Cardiovascular Medicine Journal, 2010, Volume 4 91
thermore, the proliferation of macrophages and increased
formation of foam cells enhances secretion of TNF-alpha in
the endothelium, perpetuating this vicious atherogenic cycle
. TNF-alpha also upregulates membrane expression of
vascular cell adhesion molecule-1 , which plays a well
established role in atherosclerosis  and it precedes the
development of thickened intima with foam cell lesions .
Apart from these in vitro observations, increased expression
of serum TNF-alpha has been found in patients with athero-
sclerotic complications in population studies [59, 60]. In RA
patients, TNF-alpha enhances prothrombotic states such as
dyslipidemia , but, most importantly, pooled evidence
reveals that anti-TNF-alpha treatment may be in part respon-
sible for reducing the risk for CVD events in RA . Re-
cent studies also reveal that TNF-alpha is involved in the
more advanced processes of atherosclerosis, specific to for-
mation of an advanced lesion via the inhibition of endothe-
lial progenitor cells . In RA patients, endothelial pro-
genitor cell numbers are decreased compared to the healthy
population , a phenomenon which reverses via blockade
of TNF-alpha .
IL-6, IL-1 and TNF-alpha levels, which can trigger the
acute-phase response resulting in high CRP, and have direct
effects on the endothelium that may enhance atherosclerotic
processes. As such, uncontrolled inflammation is thought to
be amongst the prime factors involved in the accelerated
atherosclerosis in RA [1, 2].
Inflammation in RA associates with dramatic increases of
THE EFFECTS OF EXERCISE ON VASCULAR
the most important non-pharmacological interventions in
both preventing and rehabilitating patients with non-
Increasing physical activity has been identified as one of
communicable chronic diseases such as CVD. This is
because exercise reverses endothelial dysfunction and has
important anti-atherogenenic and anti-inflammatory effects
(Fig. 1). Most importantly, even compared to standardized
interventional strategies, exercise may improve survival at
lower treatment costs .
Endothelial Function and Exercise
system, both acutely and in the long term. These stimuli
intervene and beneficially modify endothelial cell phenotype
. The acute effects of exercise are characterized by sig-
nificant increase in blood flow pertaining to the increased
metabolic demands of the exercizing muscles and are closely
related to the muscle fibre type recruitment (slow or fast
twitch) as well as the duration and intensity of exercise .
The major mechanism responsible for exercise-induced
hyperaemia is endothelial NO  and occurs due to the
increased endothelial eNOS protein expression  as well
as eNOS activation via Akt phosphorylation . Exercise
acutely increases local expression of endothelial progenitor
cells (endothelial repair) as well as cultured/circulating angi-
ogenic cells which promote angiogenesis and endothelial
growth . Shear stress which is the result of exercise-
induced blood flow enhances intracellular mechanisms
which increase eNOS transcription and upregulate anti-
oxidative mechanisms. Specifically, tyrosine kinase c-Src
acts to increase eNOS and extracellular superoxide dismu-
tase expression, both of which relate to better endothelial
function . In addition, it has been well-established that
shear stress increases the expression of PG I2, a vasodilator
and inhibitor of platelet aggregation . Furthermore, vas-
cular endothelial growth factor, which regulates capillary
supply and exercise-induced angiogenesis, is significantly
increased in response to exercise in both untrained and
Exercise exerts significant effects on the endothelial
Fig. (1). The effects of physical activity on endothelial function, atherosclerosis and inflammation.
Reverses Endothelial Dysfunction
Increased Blood Flow
Improved anti-Oxidative Mechanisms
Increased Endothelial Progenitor Cells
Increased Vascular Endothelial Growth
Increased anti-Oxidative Capacity
Decreased adhesion molecules
Decreased C-Reactive Protein
Reduced Adipose Tissue Size
Decreased expression of pro-inflammatory
Anti-inflammatory action of interleukin-6
92 The Open Cardiovascular Medicine Journal, 2010, Volume 4 Metsios et al.
trained individuals . In the long term, the above
mentioned physiological responses promote vascular
remodelling, a necessary adaptation for improved oxygen
exchange and blood flow delivery . These long-term
improvements are characterized by improved NO bioavail-
ability and/or endothelium-dependent vasodilation that may
even reverse age-related vascular deterioration [75, 76].
Improved endothelium-dependent vasodilation in response to
long-term exercise is a consistent finding in both healthy
 and disease populations .
Anti-Atherogenic Effects of Exercise
mRNA expression increases while ET-1 decreases [79, 80],
while concomitant changes involve down-regulation of
vascular cell adhesion molecule 1 . Oxidative stress
accelerates atherogenesis via oxidation of retained low-
density lipoprotein, enhancing formation of foam cells .
An important long-term adaptation to exercise is the im-
provement in the anti-oxidative capacity of the human body,
i.e. resistance to oxidative stress . In particular, the en-
zymes catalase and superoxide dismutase which decompose
reactive oxygen species are significantly increased as a result
of habitual physical activity . Increased eNOS in the
endothelium increases anti-oxidant molecules such as super-
oxide dismutases 1 and 3 and angiotensin receptor type 2 and
decreases oxidative molecules such as NADPH oxidase
and angiotensin receptor type 1 . Endothelial expression
of adhesion molecules, selectins and MCP-1, all of which
promote atherosclerosis, also decreases .
Acutely, due to exercise-induced shear stress, eNOS
Anti-Inflammatory Effects of Exercise
profound anti-inflammatory effects in the healthy population
as well as patients with chronic diseases . In population-
based studies, regular physical activity is consistently associ-
ated with a reduction in CRP levels [87, 88] which is also the
case in patients with RA [89, 90]. The exact mechanisms
whereby regular exercise reduces CRP have not yet been
fully elucidated, but it seems that this association may exist
via exercise-induced reduction in hypertension, triglycerides,
and apolipoproteins, factors which are directly related to
CRP concentration . Most importantly, exercise reduces
adipose tissue which is largely responsible for secretion of
IL-6, a major trigger for hepatic production of CRP [92, 93].
However, these are physiological responses of moderate
physical activity/exercise, whereas strenuous exercise
may acutely promote an inflammatory response. CRP may
increase immediately after prolonged strenuous exercise but
returns to basal levels after approximately 48 hours, while
this proportionate rise in CRP depends on the intensity of the
exercise and the subsequent exercise-induced muscle dam-
age [94, 95].
Physical activity and/or moderate intensity exercise have
tissue is responsible for the production of myokines (muscle
cytokines) suggesting that muscle is also an endocrine organ
. Muscle contractions regulate expression of specific
cytokines such as IL-6, -8, -10, and -15, as well as IL-1
receptor antagonist and TNF-alpha [96-98]. It is thought that,
although IL-6 is predominantly a pro-inflammatory cytokine,
Recent advances in muscle physiology reveal that muscle
it may also have under certain circumstances anti-inflamma-
tory properties . In that light, and based on the fact that
IL-6 increases exponentially with acute exercise up to 100
times compared to resting levels and returns to resting levels
post-exercise , it has been suggested that IL-6 is the
most important cytokine that induces the anti-inflammatory
effects of exercise . In contrast, pro-inflammatory cyto-
kines IL-1b and TNF-alpha do not generally increase in re-
sponse to moderate intensity exercise , whereas anti-
inflammatory cytokines such as IL-1ra and IL-10, signifi-
cantly increase [99, 102]. Interestingly, in response to regu-
lar exercise, IL-6 exerts its anti-inflammatory effects by
primarily inhibiting the expression of TNF-alpha .
Data have demonstrated that IL-6 inhibits lipopolysacharide-
induced TNF-alpha in human blood mononunclear cells
, whereas TNF-alpha levels are overexpressed in IL-6
deficient mice . Recently, the transcriptional coactiva-
tor PGC1a has also attracted attention as it suppresses
various inflammatory responses and regulates the effects of
exercise  by coactivating transcription factors involved
in biogenesis of mitochondria, oxidative phosphorylation
and fatty acid oxidation [106, 107]. All these biological
changes in cytokine expression in response to exercise, lead
to beneficial long-term effects. Indeed, a consistent finding
in the literature is that regular exercise relates to decreased
systemic inflammation in both healthy and diseased popula-
tions [88, 89, 108, 109].
EFFECTS OF EXERCISE ON CVD IN RA
initially led to the notion that RA patients should rest, as
exercise may enhance joint damage . However, during
the last decade substantial evidence deriving from random-
ised trials reveals that exercise inhibits the progression of the
disease and improves both wellbeing and functional ability
of RA patients . This is due to normal physiological
processes which develop as a result of exercise training such
as the improved muscle co-ordination and hypertrophy, re-
duced fat mass and better immune function. Patients that
indeed have to refrain from specific exercises are those with
extensive structural damage; in this occasion load of the
damaged joints has to be avoided and can be replaced with
alternative types of exercise. The beneficial effects of differ-
ent exercise training types on disease activity and severity
have been confirmed several times by various studies [110,
111] and hence, based on these evidence, exercise has now
been incorporated in the management of RA . It is,
therefore imperative that RA patients embark on exercise
training programmes. Although exercise is beneficial, in-
creasing physical activity in this population may prove diffi-
cult  perhaps due to the frequent advice from rheuma-
tology specialists to RA patients, that exercise may exacer-
bate disease symptoms . However, data from published
studies  of excellent quality as well as anecdotal
evidence, reveal that RA patients should and can exercise at
high intensities, and this is beneficial for various outcomes
of this chronic disease. Moreover, studies have collectively
shown that overall the adherence rates in exercise pro-
grammes can be high, presumably due to the fact that
the significant improvements achieved via exercise promote
self motivation .
The extensive damage of the joint structures in RA has
Vascular Function and Inflammation in Rheumatoid Arthritis The Open Cardiovascular Medicine Journal, 2010, Volume 4 93
found that, surprisingly, no studies have investigated the
effects of exercise on CVD outcomes in this population .
However, given the ample evidence of the beneficial effects
of physical activity/exercise on inhibiting disease progres-
sion and improving disease outcomes, we have proposed a
model in which exercise should be incorporated in the man-
agement of the disease in order to prevent CVD, which is
highly prevalent in this population. In this model, we suggest
that effective treatment and control of inflammation should
precede involvement in exercise in order to prohibit further
damage and discomfort for the RA patient. Various drugs are
available for patients with RA, including biological agents
such as TNF-alpha, which target different biological path-
ways for inhibiting disease progression. Overall, medication
strategies are effective in ameliorating disease activity (i.e.
reduced expression of pro-inflammatory cytokines and
CRP), a phenomenon that is also apparent as a response to
exercise training. Nevertheless, given the lack of evidence
regarding the effects of exercise on RA, potential changes in
medication should always be based on robust clinical out-
comes and patient feedback.
In a systematic review on exercise, CVD and RA, we
are included in the management of many chronic diseases. In
RA, where patients experience increased prevalence of
CVD, exercise may be even more important due to its anti-
atherogenic and anti-inflammatory effects [17, 99]. The
majority of studies on RA and exercise investigated the ef-
fects of physical activity/exercise regimens on improving
RA-related disease outcomes. We have recently shown that
physically inactive RA patients have worse CVD risk profile
compared to physically active patients. In this cross-sectional
study, we have investigated classical and novel risk factors,
the prevalence of established CVD as well as the risk as-
sessment of developing CVDs in physically active as well as
inactive RA patients. Regarding the novel CVD risk factors,
our results revealed that parameters associated with vascular
function (e.g. von Willebrand factor), fibrinolysis athero-
genesis (lipoproteins), pro-inflammatory cytokines, and CRP
were markedly improved in patients who demonstrated
increased levels of physical activity . However, more
research is required in order to investigate the potential
associations of exercise on vascular function and CVD risk
in this population as well as the mechanisms that underlie
Exercise involvement and/or increased physical activity
between inflammation, vascular dysfunction and atheroscle-
rosis. In RA, although evidence exists to support this asso-
ciation for atherosclerosis, the results are equivocal at least
for endothelial dysfunction, potentially due to the differences
in the methodological designs that do not take into account
important factors that could influence endothelial function
and atherosclerosis in RA. In addition, exercise has a protec-
tive effect via inhibiting the expression of inflammatory
markers and their effects on both endothelial dysfunction and
promotion of atherosclerosis. Future studies in RA should
specifically investigate the effects of exercise regimes on
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Received: November 20, 2009
Revised: November 30, 2009 Accepted: December 14, 2009
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