Vascular endothelium  role in chronic inflammatory disease
ABSTRACT
Serafim Kiriakidis1,2,*
he vascular endothelial lining of blood vessels plays a key  target-effector role in vivo,
Tintegrating the body s response to inflammatory cytokines, chemokines and growth fac-
tors (derived from both endothelial cells themselves and from other cells such as leukocytes Ewa M. Paleolog1,2
and fibroblasts), to allow leukocyte activation, adhesion and extravasation from the flowing
blood into underlying tissue. Endothelial proliferation, through the process of angiogene-
1
Kennedy Institute of Rheumatolo-
sis, results in an increased cell surface area for these events to occur, and further functions
gy, Nuffield Department of Orthopa-
to deliver oxygen and nutrients, and to remove waste products. In addition to playing an
edics, Rheumatology and Musculo-
important role in physiology, the endothelium is thus an active participant in inflammatory
skeletal Sciences, University of Oxford
pathologies. One of the best understood diseases in which inflammation and angiogenesis
2
Department of Medicine, Imperial College
play a part is rheumatoid arthritis (RA). Blockade of the inflammatory cascade in RA has
London
significant consequences for the vasculature, highlighting the links between reducing endo-
thelial activation and therapeutic benefit in chronic inflammatory disorders.
*
Kennedy Institute of Rheumatology, Nuffield
Department of Orthopaedics, Rheumatology
INTRODUCTION
and Musculoskeletal Sciences, University of
Oxford, Roosevelt Drive, Headington, Oxford,
The human vascular endothelial lining of blood vessels, which covers the
OX3 7FY, UK; e-mail: serafim.kiriakidis@
body s network of arteries, veins, capillaries and lymphatics, was in the past
kennedy.ox.ac.uk
thought to be merely an inactive barrier between the circulation and underlying
tissues. However, it is now clear that despite its relatively small total mass, en-
Received: September 14, 2013
dothelium actively participates in physiology and pathology in vivo. Endothelial
Accepted: September 14, 2013
cells produce mediators regulating blood flow, and influence coagulation and
fibrinolysis, usually presenting a non-thrombogenic surface to flowing blood.
Key words: endothelium, inflammation, arthri-
tis, cytokines, angiogenesis
Furthermore, the endothelium plays a role in the process of cell recruitment,
through expression of cytokines and chemokines, thus affecting the activation
Abbreviations: CRP  C-reactive protein; FIH-
status of leukocytes. Finally, endothelial cells play a central role in the process of
1  factor inhibiting HIF-1; HIF  hypoxia-in-
angiogenesis, which is vital for efficient supply of oxygen and nutrients to tissue,
ducible factor; ICAM-1  intercellular adhe-
and for removal of waste products.
sion molecule-1; IL  interleukin; PHD  pro-
lyl hydroxylase domain-containing enzyme;
Vascular endothelium thus fulfills a vital homeostatic function and acts as a RA  rheumatoid arthritis; TNFÄ…  tumour
necrosis factor Ä…; VCAM-1  vascular cell ad-
rapid response facility in situations of inflammation, injury or infection. Indeed
hesion molecule-1; VEGF  vascular endothe-
endothelium plays an important target-effector role in many diseases associated
lial growth factor
with inflammation. Such diseases include diabetes type 1, where microvascular
and macrovascular complications combine with activation of the immune sys-
tem and inflammation. In chronic airway disease, inflammation leads to chan-
ges in the airways and obstruction of airflow, but other events include vascular
remodelling and angiogenesis. Other disorders, such as systemic lupus erythe-
matous, atherosclerosis and inflammatory bowel diseases, also involve immune
system activation and enhanced blood coagulation in association with pro-in-
flammatory cytokine expression.
Rheumatoid arthritis (RA) is a prototypical inflammatory disease, in which
angiogenesis and changes in oxygen tension interact with inflammation to cul-
minate in the features of joint and cartilage destruction. Since the pathogenesis
of RA is relatively well understood, RA can serve as a paradigm for understan-
ding the role of the vasculature in inflammation, particularly in the light of ob-
servations using therapies targeting aspects of the inflammatory process in RA,
such as anti-tumour necrosis factor Ä… (TNFÄ…) biologicals. The involvement of
the vasculature in RA pathogenesis will be discussed in detail in the following
sections.
RHEUMATOID ARTHRITIS  A PROTOTYPICAL INFLAMMATORY
DISEASE WITH VASCULAR INVOLVEMENT
RA is a common human disease, affecting about 1% of the population in
most parts of the world, and is characterized by inflammation of the synovial
membrane which lines the joint spaces, leading to the localized invasion and
Postępy Biochemii 59 (4) 2013 415
destruction of underlying cartilage and bone. Every year in phocytes and generation of mediators of humoral and cellu-
the United Kingdom there are approximately 20 000 new lar immunity needs to occur in the peripheral lymphoid or-
cases of RA, which is more common in women than men gans, primarily lymph nodes and spleen. T lymphocytes cir-
by a factor of 3:1 [1]. The clinical presentation can vary in culate between non-lymphoid tissues and the lymph nodes,
terms of severity and the age of onset, although the peak of entering through the afferent lymphatic blood vessels and
RA onset occurs between the fifth and sixth decades of life. across the high endothelial venules, and exiting via efferent
Patients display painful, stiff and swollen joints, and usual- lymphatic vessels. This continuous lymphocyte trafficking
ly present with a symmetrical polyarthritis, predominantly across endothelium enables the antigen-sensitive cells to be
involving the small joints of the hands and wrists, as well as exposed to their specific antigen, prompting clonal expan-
the metatarsophalangeal joints, ankles and knees. RA is as- sion. Blood vessels thus allow recruitment of the activated
sociated with a range of non-articular symptoms, including lymphocytes to specific sites, which is promoted further by
inflammatory nodules, vasculitis and pericarditis, together vasodilation. An increase in vessel density through angioge-
with involvement of the lungs and nervous system, depres- nesis further increases the endothelial surface area available
sion and anaemia. Furthermore, the standardized mortality for the ingress of cells and molecules to the site of inflam-
ratio for patients with RA is more than 1.5 2.5-fold higher mation, amplifying and maintaining the immune response.
than for the general population. The major cause of mor-
The involvement of endothelium in the pathogenesis of
tality (more than 40% of deaths) is cardiovascular disease,
RA can also be inferred from observations that RA is as-
including ischemic heart disease and heart failure [2]. A to-
sociated with vascular and haematological abnormalities
tal of 10 million working days were lost in 2006 2007 in the
(such as anaemia). The swollen joints which occur in RA pa-
UK due to musculoskeletal conditions such as RA, second
tients suggest altered vascular permeability, with increased
only to stress, depression and anxiety, representing a signi-
plasma extravasation and oedema formation. Interestingly,
ficant economic impact due to lost production. RA patients
a recent study has documented the presence of immature
of working age are significantly more likely to stop work on
blood vessels in RA synovium. Comparison of the staining
health grounds than matched controls. RA thus imposes a
patterns for CD31 and the pericyte marker Ä…-smooth musc-
significant social and economic burden, due to loss of ear-
le cell actin revealed a significant fraction of CD31-positive
nings and medical expenses, apart from adversely affecting
but Ä…-smooth muscle cell actin-negative cells in RA tissue
quality of life.
when compared to osteoarthritis or control tissue [8]. This
In spite of many years of intensive investigation, the altered vascular signal in RA synovium was also detected
cause of RA remains unknown, although current thinking using Doppler ultrasound [9,10]. Studies using mouse mo-
favours the concept of a multi-factorial disease, in which dels of RA have also shown vascularised synovium in arth-
contributory genetic factors, including shared epitope alle- ritic mice [11] (Fig. 1).
les of the human leukocyte antigen and a polymorphism of
protein tyrosine phosphatase N22 [3,4], combine with envi- Therefore, activation of an effective immune response,
ronmental factors (such as smoking), sex hormones, and enhanced leukocyte activation and extravasation, expres-
perhaps an infectious agent or other immune-activating fac- sion of chemokines, and increased angiogenesis, possibly
tor, to initiate an autoimmune response that culminates in a leading to formation of immature and highly permeable
disease with inflammatory and destructive features [5]. As
mentioned, the primary site of inflammation is the synovial
lining of the closed spaces of articular joints. The normal sy-
novium is generally 1 3 cell layers thick and is composed
of loosely associated macrophage- and fibroblast-like cells,
as well as vascular endothelial cells. In RA, the synovium
is altered to a thickened tissue several cell layers thick, and
becomes infiltrated by blood-derived cells, including T cells,
B cells and macrophages. Subsequently the synovium beco-
mes locally invasive at the synovial interface with cartila-
ge and bone. Progressive destruction of cartilage and bone
eventually combine to produce deformities and functional
deterioration and profound disability in the long term [6].
Of relevance to this review, the term  vascular rheumato-
logy has been coined, to emphasise the importance of mi-
crovascular and macrovascular endothelium in RA and in
other rheumatic disorders. Figure 1. Synovial vascularity in an in vivo model of arthritis. Arthritis was indu-
ced in mice using bovine collagen and arthritis development and severity were
monitored daily [11]. Serial sections of paw tissue from healthy (A, C) and severe-
ROLE OF ENDOTHELIUM IN INFLAMMATORY DISEASE
ly arthritic (B, D) mice were stained with either (A, B) haematoxylin and eosin or
(C, D) with anti-CD31 antibody and counter-stained with haematoxylin. Images
show the metatarsal joint of mouse paws. The healthy section demonstrates a nor-
RA, as an autoimmune disease, is characterized by the
mal joint architecture without signs of inflammation or bone destruction. In the
presence of circulating auto-antibodies, including some
arthritic joint, synovial hyperplasia, blood vessels (CD31-positive), inflammatory
cell infiltration, and loss of cartilage and bone are evident. Abbreviations: B 
that bind with high affinity to human endothelial cells [7].
bone; C  cartilage; S  synovium; JS  joint space.
Integration of antigen-presentation, amplification of lym-
416 www.postepybiochemii.pl
blood vessels, all point to the underlying role of inflamma- ted improved specificity compared to a conventional tracer
tion-mediated vascular endothelial activation in RA, which for bone and joint, and specificity for targeting active joint
will be discussed in more detail in subsequent sections. inflammation [15]. In our laboratory, we recently demon-
strated that imaging of anti-E-selectin in vivo could detect
LEUKOCYTE-ENDOTHELIAL INTERACTIONS IN RA
endothelial activation in models of arthritis and could be
applied to quantify disease and investigate the effects of no-
The cellular infiltration which is a characteristic of RA
vel therapies [16]. Elevated levels in RA of soluble forms of
synovium suggests that activation of endothelium, together
E-selectin, ICAM-1 and VCAM-1 have also been described.
with expression of leukocyte adhesion molecules, as well as
Synovial membrane and synovial fluid T cells display an
of cytokines and chemokines, is likely to be involved in RA
enhanced capacity to interact with purified E-selectin and
pathogenesis. Adhesion of leukocytes to vascular endothe-
VCAM-1, relative to peripheral blood lymphocytes from
lium in vivo must overcome the normal vascular mobility
either the same patients or from healthy donors, due to
of circulating cells and result in a localized arrest of leu-
increased levels of VLA-4Ä…, the counter-ligand for VCAM-
kocytes at relevant sites. Endothelial cells resembling high
1. In addition, synovial fluid lymphocytes show higher
endothelial venules, which control lymphocyte migration
expression of other integrins such as CD29, VLA-1Ä…, VLA-
into organized lymphoid tissues, have been observed in RA
5Ä… and VLA-6Ä… [17,18]. Accumulation of T cells in RA sy-
synovium. These synovial microvascular endothelial cells
novium thus appears to result from elevated expression of
acquire a cuboidal morphology, and become fenestrated
adhesion receptors on synovial microvascular endothelium,
[12], suggesting specialised mechanism(s) regulating leuko-
leading to the selective emigration of memory T lympho-
cyte extravasation into joint tissue.
cytes, which may bear enhanced levels of ligands for these
adhesion molecules as a result of a previous activation step.
Inflammatory cytokines such as TNFÄ… and interleukin
Other adhesion molecules present on synovial endothelial
(IL)-1, which play a central role in RA pathogenesis, have
cells include CD31, vascular adhesion proteins (VAP)-1 and
the potential capacity to regulate many of the events occur-
VAP-2 and CD146 [19].
ring in the RA microvasculature, including leukocyte extra-
vasation and chemotaxis [13]. TNFÄ… is a fundamental indu- Moreover, endothelial cells are a source of a range of pro-
cer of endothelial cell responses, and both TNFÄ… receptors -inflammatory cytokines, including IL-1, IL-6 and granu-
CD120a/TNF-R1 and CD120b/TNF-R2 have been detected locyte macrophage colony-stimulating factor. Many of the
on RA synovial endothelial cells. In RA, endothelial cells features of the rheumatoid synovial environment suggest
express numerous cytokine-inducible adhesion molecules, possible roles for chemoattractant cytokines, in that the lar-
including E-selectin [14], vascular cell adhesion molecule ge number of infiltrating leukocytes, especially the accumu-
(VCAM)-1 and intercellular adhesion molecule (ICAM)-1. lation of monocyte/macrophages and lymphocytes, could
99m
For example, scintigraphy utilizing a Tc-anti-E-selectin- in part be a response to the elaboration of chemokines. En-
-Fab was used to image synovitis in RA, and demonstra- dothelial cells secrete and present on cell surface proteogly-
cans chemokines of both CC and
CXC sub-sets, in particular IL-8/
CXCL8, monocyte chemoattrac-
tant protein-1/CCL2, RANTES/
CCL5 and GroÄ…/CXCL1 [20]. The
ability of endothelium to captu-
re chemokines ensures that me-
diators become anchored on the
endothelial surface, to enable a
relatively high concentration of
chemoattractants close to the ves-
sel wall, and hence to temporally
and spatially regulate activation
of circulating cells (Fig. 2).
ENDOTHELIUM AND
ANGIOGENESIS IN RA
Another feature of the syno-
vium in RA is altered density of
sub-lining capillaries and post-
-capillary venules, supporting
an important role for angioge-
nesis. Endothelial cells, exposed
to inflammatory cytokines and
Figure 2. The vasculature in RA: cause and consequence. In RA, infiltration by blood-derived cells, hyperproliferation
of synovial fibroblasts and angiogenesis occur. A self-perpetuating cascade of events is triggered, due to expression of
growth factors, respond by alte-
cytokines, growth factors and chemokines. Fibroblast proliferation results in synovial hypoxia, resulting in expression
ring their proliferation rate and
of hypoxia-derived factors such as VEGF. Increased angiogenesis further amplifies the inflammatory cascade.
cellular metabolism, to form new
Postępy Biochemii 59 (4) 2013 417
blood vessels. Blood vessels therefore fulfil an important low density lipoprotein levels. The acute phase response in-
role in RA, fuelling synovial expansion and infiltration by flammatory marker CRP is a risk factor for atherosclerosis,
inflammatory cells from the blood, by supplying oxygen and CRP levels are markedly elevated in RA, as part of the
and nutrients necessary for cell metabolism and division, as ongoing systemic inflammatory processes, suggesting that
well as by bringing in leukocytes and signalling mediators such an augmented inflammatory burden may be linked to
such as cytokines and growth factors [21-25]. The number of the increased cardiovascular risk in RA [39,40].
synovial blood vessels has been found to correlate with sy-
Interestingly, the process of vasodilation is altered in
novial cell hyperplasia and indices of joint tenderness [26].
RA. Herbrig et al., who studied blood flow in the forearm
Endothelial cells lining blood vessels within RA synovium
following infusion of acetylcholine, showed that vaso-
express cell cycle-associated antigens, and indices of endo-
dilatation was significantly reduced in RA patients [41].
thelial turnover are increased in synovia from patients with
A more recent study examined the relationship betwe-
RA compared with non-inflamed controls. A morphometric
en flow-mediated endothelium-dependent vasodilata-
study also suggested that capillaries are distributed more
tion and carotid artery intima-media wall in RA patients
deeply in RA synovium [27], and endothelial proliferation
without clinically evident cardiovascular disease, and
was shown to be increased in synovium from patients with
found that carotid intima-media thickness values were
RA [28].
higher and flow-mediated vasodilatation were lower in
Many of the cytokines and growth factors expressed individuals with long-standing RA compared to those
in RA have the potential to stimulate endothelial proli- with shorter disease duration [42]. Another recent study
feration [21]. For example, serum levels of vascular en- reported arterial stiffness to be associated with endothe-
dothelial growth factor (VEGF) are markedly elevated in lial dysfunction and atherosclerosis in patients with auto-
RA, relative to either patients with osteoarthritis or nor- immune diseases such as RA [43].
mal controls, and correlate with levels of inflammatory
markers such as C-reactive protein (CRP). Serum VEGF Furthermore, although blood vessel density is altered in
levels have also been shown to correlate with blood flow RA, and angiogenesis has generally been thought to un-
in wrist synovium of patients with RA [29]. Expression derlie these changes, endothelial progenitor cells may also
of VEGF by RA lining layer cells has been reported, and play a role. Endothelial progenitor cells have been found
microvascular endothelial cells in the vicinity of VEGF- to differentiate into endothelial cells, express classic en-
-positive cells express VEGF receptors [30]. Conditioned dothelial cell markers, including CD31, CD34 and VEGF
medium from synovial tissue explants was shown to be receptor 2 and to exhibit endothelial cell properties, such
mitogenic for endothelial cells, an activity reduced by as expression of the endothelial-specific isoform of nitric
anti-VEGF antibody [30], further supporting the concept oxide synthase (eNOS) and the adhesion molecule E-selec-
of an important role for endothelium and VEGF in RA. tin. The endothelial cells present in the circulation are ca-
In addition to synovial expression of VEGF, circulating pable of integrating into vessel walls, and it is these endo-
(serum) levels of VEGF are increased, and correlate with thelial progenitor cells which may link RA with increased
inflammatory response markers [31,32]. Treatment of cardiovascular morbidity and mortality. In RA synovium,
murine arthritis using anti-VEGF antibody delayed dise- CD34/VEGF receptor 2-positive cells have been described
ase onset and reduced symptoms of arthritis [33,34]. Tar- found in apposition to synovial blood vessels [44]. Bone
geting VEGF receptors, specifically VEGF receptor 1, also marrow-derived CD34-positive cells, which can expand
resulted in disease amelioration [35-37]. In summary, the into CD31- and von Willebrand factor-expressing cells,
invasive synovium in RA is highly vascularised, and mo- have been reported to be generated at a higher rate from
lecules such as VEGF are expressed, and are thus likely bone marrow samples taken from RA patients, compared
to significantly modulate endothelial activation (Fig. 2). to normal subjects. Furthermore, the capacity of bone mar-
row-derived cells from RA patients to progress into endo-
CARDIOVASCULAR DISEASE IN RA  ROLE
thelial cells correlated with synovial microvessel density
OF ENDOTHELIAL DYSFUNCTION
[45]. In a parallel to the situation seen with coronary artery
disease and ischemic heart disease patients, endothelial
The mortality of patients with severe RA is equivalent to progenitor cells numbers are decreased in the peripheral
that of individuals with triple vessel coronary artery dise- blood of RA patients compared with healthy individuals.
ase, with the major cause of mortality (more than 40% of Circulating endothelial progenitor cells (CD34/VEGF re-
deaths) being cardiovascular disease, including ischemic ceptor 2-positive) were lower in patients with active RA
heart disease and heart failure [38]. Endothelial dysfunction than in individuals with inactive disease or healthy con-
is known to occur in RA, providing a possible link betwe- trols [46]. The observation of reduced circulating endo-
en these seemingly disparate pathologies. The endothelial thelial progenitor cells in RA patients was confirmed in
lining of blood vessels has a critical function in atheroscle- another study, which demonstrated reduced migration of
rosis, serving as the site of initial injury and leukocyte ad- endothelial progenitor cells from RA patients in response
hesion/migration. Maintenance of an intact vascular lining to VEGF, suggesting that the functional capacity of these
and an uninterrupted vascular supply is thus critical in the cells may be attenuated in RA. Endothelial progenitor cells
prevention of the cascade of events which trigger acute from RA patients exhibited only modest adhesion to en-
coronary syndromes such as myocardial infarction. Many dothelial cells stimulated with TNFÄ…, compared with cells
studies have reported an association between RA and tra- from healthy subjects, despite comparable levels of adhe-
ditional cardiovascular risk factors such as cholesterol and
418 www.postepybiochemii.pl
sion to unstimulated endothelial cells or matrix proteins therapy in RA significantly reduced 111In-labelled granulo-
such as fibronectin or laminin [41]. cyte migration into affected joints. There was a simultane-
ous reduction in the numbers of infiltrating synovial CD3-
The above data suggest enhanced recruitment from pe-
-positive T cells, CD22-positive B cells, and CD68-positive
ripheral blood of endothelial progenitor cells to RA syno-
macrophages [47].
vium. This might then lead to increased RA synovial blood
vessel formation, perpetuating disease. Furthermore, incre- In later studies, ultrasonography has been used to me-
ased endothelial progenitor cell trafficking to the synovium asure synovial inflammation and vascularity. These inve-
would be paralleled by reduced peripheral blood endothe- stigations have shown that assessment of synovial thicke-
lial progenitor cells in RA, which could be a significant fac- ning and vascularity at baseline was an early and sensitive
tor in the increased cardiovascular morbidity and mortality measure of response to treatment and radiological changes
seen in RA. to anti-TNFÄ… antibody [10]. Indeed ultrasonographic me-
asures of synovial thickening and vascularity were able to
INSIGHTS FROM STUDIES USING TNFÄ… INHIBITORS
discriminate between RA patients receiving anti-TNFÄ… or
placebo with greater sensitivity than conventionally used
Over the last 25 years, major advances in the understan- outcome measures of change in disease activity that depend
ding of the pathogenesis of RA, based on bench-bedside stu- on the use of clinical evaluation, such as the numbers of ten-
dies of human tissue and animal models of disease, have led der and swollen joints.
to the identification of a number of new molecular targets
for intervention. TNFÄ… mediates many inflammatory and In the context of effects on endothelial progenitor cells,
immunoregulatory activities relevant in RA. The concept of RA patients with active disease treated with TNFÄ… inhibi-
TNFÄ… as a therapeutic target was put forward by Feldmann tors showed a restoration of circulating endothelial progeni-
and Maini in the late 1980s, and to date several biological in- tor cells levels to those seen in healthy control subjects. This
hibitors of this cytokine have been approved for use in RA. effect was not seen in patients with active RA but receiving
conventional disease-modifying drugs [46]. A more recent
Clinical trials of these inhibitors, which commenced in study directly examined the effect of anti-TNFÄ… antibody
the late 1990s, have shed considerable light on the role of on endothelial progenitor cell numbers and function. A si-
the endothelium in RA. The first Phase I/II study was an gnificant increase in endothelial progenitor cell levels and
open-label trial of a single intra-venous infusion of inflixi- adhesion was seen after 2 weeks of anti-TNFÄ… treatment,
mab (Remicade"!), a chimeric mouse Fv-human IgG1k an- together with an improvement in the disease activity score.
tibody that binds both soluble and membrane-bound TNFÄ… Interestingly, a significant correlation was seen between the
with high affinity, in long-standing active RA patients who extent of clinical response and the degree of increase in en-
had failed all prior therapy. The results were striking, sho- dothelial progenitor cell numbers [49]. The cardiovascular
wing reductions in pain and morning stiffness, swollen and risk profile is also altered after TNFÄ… blockade. Treatment
tender joint counts, and CRP levels. Since trafficking into with anti-TNFÄ… antibody significantly increased concentra-
the synovium of blood-borne cells is a feature of RA, and tions of fibrinogen and HDL-cholesterol, whereas LDL and
since TNFÄ… is one of the most potent regulators of leukocyte triglyceride levels were unchanged, and no changes in lipid
trafficking, it seemed reasonable to hypothesize that anti- profile were seen in the placebo group [50]. Similarly, treat-
TNFÄ… antibody treatment might regulate synovial infiltra- ment with TNFÄ… inhibitors has been reported to reduce the
tion. This question has been addressed over the years with incidence of first cardiovascular events in patients with RA
increasingly sophisticated studies, which started with the [51].
measurement of soluble adhesion molecules, which could
be quantified in serially acquired serum samples. Levels of Given that serum VEGF levels were elevated in patients
serum E-selectin and ICAM-1 were decreased after infusion with RA, it seemed reasonable to suppose that treatment of
of anti-TNFÄ… antibody, and the extent of the decrease was RA with anti-cytokine biologicals might modulate VEGF
significantly higher in patients in whom a clinical benefit expression. To examine this hypothesis, we measured se-
of anti-TNFÄ… was observed. Moreover, a significant reduc- rum VEGF levels in RA patients treated with anti-TNFÄ… an-
tion was observed in CD3- and CD68-positive cells in the tibody. In patients receiving a single infusion of anti-TNFÄ…,
synovium, as well as a decrease in synovial expression of serum VEGF levels were markedly reduced. Treatment of
VCAM-1 and E-selectin [47,48]. Later studies showed that RA patients with a combination of multiple infusions of
synovial and serum chemokines (IL-8/CXCL8 and mono- anti-TNFÄ… and methotrexate resulted in a more prolonged
cyte chemoattractant protein-1/CCL2) were decreased [47]. decrease in serum VEGF levels relative to patients who re-
These reductions correlated with a rapid and sustained in- ceived anti-TNFÄ… antibody alone [32]. As discussed, the
crease in blood lymphocyte counts [48]. presence or density of immature vessels is significantly in-
creased in RA patients, and interestingly, immature vessels
Direct evidence of an effect on cell trafficking came from
were depleted in response to anti-TNF therapy, highligh-
elegant studies using gamma camera imaging of radioacti- ting the co-dependency of angiogenesis and inflammation
vely labelled polymorphonuclear cells. Patients with long- [8]. Furthermore, as mentioned earlier, endothelial dysfunc-
standing RA received a single infusion of anti-TNFÄ… anti- tion is a feature of RA. Impaired flow-mediated vasodila-
body, and the articular localization of autologous polymor- tion in RA patients was reversed following TNFÄ… inhibition
phonuclear cells, separated in vitro and labelled with 111In,
[52,53].
was studied before and 2 weeks after treatment. Anti-TNFÄ…
Postępy Biochemii 59 (4) 2013 419
Table 1. Summary of the effects of anti-TNFÄ… on the vasculature in RA.
Cellular responses in situations of reduced ava-
ilability of oxygen are coordinated by the hypoxia-
Parameter Observed effect of anti-tnfÄ…
-inducible factor (HIF) transcription factor family.
reduced serum adhesion molecules Activation of HIF signalling leads to extensive chan-
reduced synovial adhesion molecules
ges in gene expression, to allow adaption of cells and
Leukocyte adhesion reduced synovial CD3- and CD68-positive cells
tissues to reduced oxygenation. The HIF complex
reduced leukocyte trafficking
consists of a constitutively expressed b subunit, and
increased circulating lymphocytes
an oxygen-responsive Ä… subunit. Regulation of HIF-
reduced synovial chemokines
-dependent gene expression requires Ä…-subunit ac-
Chemokine expression
reduced serum chemokines
cumulation in the cytoplasm and translocation into
the nucleus, which enables HIF-Ä… to dimerise with
reduced serum VEGF
reduced synovial vascularity
HIF-² and bind HIF co-activators, prior to binding
Angiogenesis
reduced synovial thickening
hypoxia-response elements in the target gene to ini-
reduced joint vascularity
tiate transcription. Hydroxylation by FIH-1 of aspa-
ragine residues in HIF-Ä… prevents recruitment of
reduction in elevated fibrinogen
Haematological markers reduction in elevated platelet counts
co-activators p300/CBP and thereby HIF-mediated
restoration of reduced hemoglobin
gene transcription. In contrast, prolyl hydroxylase
domain (PHD) enzymes (PHD1-3) modify HIF-Ä… by
hydroxylation of specific proline residues in HIF-Ä…,
Taken together, these observations suggest that at least enabling capture by an E3 ubiquitin ligase complex, leading
part of the clinical effectiveness of TNFÄ… blockade in RA is to proteasomal destruction of HIF-Ä…. FIH-1 and PHD1-3 be-
due to deactivation of vascular endothelium, leading to re- long to a superfamily of 2-oxoglutarate and iron dependent
duced inflammation, cell trafficking (and, as a consequence, dioxygenases, which require molecular oxygen as a co-sub-
diminished synovial cellularity) and angiogenesis, and nor- strate [58]. Thus, under conditions where O2 supply limited,
malisation of coagulation and fibrinolytic systems (summa- as is the case in RA synovium, HIF-Ä… subunits accumulate
rised in Tab. 1). This is supported by a recent finding regar- and activate gene transcription. In RA synovial tissue, HIF-
ding Certolizumab pegol, a humanised anti-TNFÄ… antibody 1Ä…-positive cells correlate with the number of blood vessels
approved for clinical use for RA. Certolizumab significantly and with inflammatory endothelial cell infiltration, prolife-
blocked TNFÄ…-induced E-selectin, VCAM-1 and ICAM-1 ration and synovitis [59].
expression on microvascular endothelial cells, as well as
chemokine expression and endothelial tube formation, and Hypoxia alters the expression of a number of endothe-
adhesion of HL60 leukaemia cells to endothelial cells [54]. lial genes, including those involved in the inflammatory
These data demonstrate that blockade of the inflammatory response. For example, increased expression of chemokines
cascade in RA, using approaches such as TNFÄ… inhibitors, such as CCL15 and IL-8/CXCL8 has been described in en-
diminishes endothelial activation and is associated with cli- dothelial cells exposed to hypoxia, suggesting that altered
nical benefit. oxygen tension may influence leukocyte activation [60,61].
Increased leukocyte adhesion to endothelial cells exposed
ENDOTHELIUM AND INFLAMMATION
to low oxygen tension has also been described [62,63], and
 INTERACTION WITH HYPOXIA
hypoxia may synergise with inflammatory cytokines such
as TNFÄ… to upregulate E-selectin and ICAM-1 [64]. Trans-
Mammalian cells and tissues are exposed to various oxy- criptomic and proteomic analyses have shown that hypoxia
gen tensions, depending on their location, frequently as low activates endothelial cells to express cytokines, growth fac-
as 5% in the case of venular endothelial cells [55]. A complex tors, extracellular matrix protein genes, collagens and mem-
interplay between altered oxygen levels and inflammation bers of the PHD family in a HIF-1-dependent manner, and
is involved in the pathogenesis of inflammatory diseases that hypoxia increased basement membrane invasion and
such as RA. The micro-environment in the inflamed joint tube formation by endothelial cells [65-67]. Of potential re-
is characterised by a low partial pressure of oxygen, first levance to RA, hypoxia increases endothelial permeability,
demonstrated more than 40 years ago. Mean synovial fluid affecting adhesion molecules such as VE-cadherin and Rho
O2 in knee joints was reported to be lower in RA patients GTPases regulating the actin cytoskeleton, such as RhoA
than in osteoarthritis patients or in healthy controls. Despite and Rac1 [68].
these intriguing observations, it was only recently that we
were able to directly measure synovial oxygen tension in Hypoxia may also affect endothelial activation indirectly,
RA patients using a highly sensitive gold microelectrode. by activating synovial cells to express factors which stimula-
We observed that synovial tissue in RA patients was inde- te endothelial cell responses. Hypoxia increases expression
ed hypoxic, with O2 lower than in non-inflamed synovium by synovial cells of pro-angiogenic factors such as VEGF
in patients without RA [56]. This hypoxic milieu leads to a [32], as well as chemokines IL-8/CXCL8 [69], CCL20 [70]
cascade of enhanced expression of hypoxia-regulated trans- and SDF-1/CXCL12 [71,72]. Increased levels of pro-inflam-
cription factors and hypoxia-responsive genes, and incre- matory cytokines such as IL-6, and of matrix-metalloprote-
ased levels of pro-inflammatory cytokines and angiogenic ase (MMP) enzymes MMP-1 and MMP-3 [69] together with
factors, establishing a link between synovial hypoxia and enhanced synovial cell invasiveness, in response to hypoxia
inflammation in RA [25,57]. have also been reported. In a recent study, interaction be-
420 www.postepybiochemii.pl
tween hypoxia, HIF and the Notch signalling pathway was are involved, such as atherosclerosis, psoriasis, diabetes and
shown to play an important role in hypoxia-induced angio- cancer.
genesis. Notch-1 was highly expressed in inflamed synovial
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Śródbłonek wyścielający naczynia krwionośne 
rola w przewlekłych chorobach zapalnych
Serafim Kiriakidis1,2,*, Ewa M. Paleolog1,2
1
Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford,
Roosevelt Drive, Headington, Oxford, OX3 7FY, UK
2
Department of Medicine, Imperial College London, UK
*
e-mail: [e-mail]
Słowa kluczowe: śródbłonek, zapalenie, zapalenie stawów, cytokiny, angiogeneza
STRESZCZENIE
Śródbłonek wyścielający naczynia krwionośne odgrywa kluczową rolę w regulacji odpowiedzi organizmu na cytokiny prozapalne, chemoki-
ny i czynniki wzrostu (pochodzące zarówno z samych komórek śródbłonkowych jak i innych komórek  np. leukocytów czy fibroblastów),
wpływając na aktywację leukocytów, ich adhezję oraz migrację ze światła naczynia do przylegających tkanek. Proliferacja śródbłonka i two-
rzenie nowych naczyń w procesie angiogenezy zwiększa powierzchnię oddziaływania z leukocytami, a jednocześnie ułatwia dostarczanie
tlenu i usuwanie zbędnych produktów przemiany materii. Oprócz ważnej roli w fizjologii, śródbłonek bierze aktywny udział w patogenezie
chorób związanych z zapaleniem. Jednym z najlepiej poznanych schorzeń, w których istotną rolę odgrywa reakcja zapalna i nasilona angio-
geneza jest reumatoidalne zapalenie stawów (RA, ang. rheumatoid arthritis). Zablokowanie odpowiedzi zapalnej w RA znacząco wpływa
na unaczynienie, potwierdzając współzależność między zahamowaniem aktywacji śródbłonka i leczeniem chronicznych stanów zapalnych.
Postępy Biochemii 59 (4) 2013 423