cardiovascular disease ( cvd ) is a serious long - term complication of chronic systemic inflammatory diseases including rheumatoid arthritis ( ra ) and systemic lupus erythematosus ( sle ) . ra is characterized by inflammation and the formation of atherosclerosis can be exacerbated and accelerated by systemic inflammation [ 1 , 2 ] . cardiovascular mortality occurs within 8 years of initial ra symptoms , but the pathophysiological process which proved to exhibit endothelial dysfunction ( ed ) probably starts much earlier [ 35 ] . ed is equal to impaired endothelial mechanism , which is first identified in ra patients by bergholm and colleagues in 2002 . the reason for ed in ra may partly be due to the altered quantity or function of endothelial progenitor cells , which are involved in vasculogenesis and vascular repair . biomarkers currently under investigation , such as circulating endothelial progenitor cells , may prove to be useful markers of ed . it may be an appropriate way to use ed as an early indicator of atherosclerosis , thereby reducing risk factor or conducting pharmacologic intervention . despite changes in the course of the disease in recent years and new therapeutic options , there is still no evidence that any particular intervention can reduce cvd risk in ra . thus , drugs targeting ed may be a potential ancillary class in treating ra patients . endothelium is a selectively permeable barrier between vascular wall and bloodstream . in noninflamed tissue , it is responsible for maintaining blood fluidity and regulating blood flow and is able to control vascular wall permeability , quiesce circulating leukocytes [ 1014 ] . these invasions include mechanical stimuli , such as pressure and shear stress , and chemical stimuli , such as hormones and locally secreted vasoactive substances . when endothelium senses stimuli , it releases factors to regulate hemostasis , cell growth , vasomotor function , and inflammatory processes . among these factors , vasodilator substances include nitric oxide ( no ) , prostacyclin , and endothelium - derived hyperpolarizing factors . ecs play a major role in the initiation of inflammatory process and have persistent effect on the process . during inflammatory process it initiates the endothelial interaction with leukocyte and platelets through loosing the ecs junctions and exports weibel - palade bodies to release the von willebrand factor and p - selectin . type ii activation is a slower but more persistent response which invokes the expression of a variety of proinflammatory cytokines and adhesion molecules . the primary mediators of type ii activation are tumour necrosis factor- ( tnf- ) and interleukin-1 ( il-1 ) derived principally from activated leukocytes . in inflammation , ecs activation induces increased vascular permeability for plasma proteins , the expression of proinflammatory cytokines , chemokines and enzymes , and an upregulation of adhesion molecules [ 1618 ] . nuclear transcription factor-b ( nf-b ) regulates the expression of adhesion molecules , such as intercellular adhesion molecule-1 ( icam-1 ) , vascular cell adhesion molecule-1 , and e - selectin that play a pivotal role in leukocyte - endothelium interactions . chemokines , such as monocyte chemoattractant protein 1 and il-8 , contribute to the inflammatory ecs response and are initiated through activation of the classical nf-b pathway . endothelium is among the first line of the body 's defense system ; it encounters and combats the perturbation of invading microbes and endogenous substances in response to tissue damage . ecs respond to these contacts by producing inflammatory mediators and expressing surface molecules , such as cd40 , cd80 , cd86 , cd134l , programmed death - ligand 1 ( pd - l1 ) , and pd - l2 . ecs also have been reported to exert their role in immune system via various receptors . nucleotide - binding oligomerization domains ( nods ) , cytosolic proteins , are able to sense microbial peptides and regulate inflammation to mediate innate immunity . specifically , ecs can secrete il-8 ( a proinflammatory cytokine ) in a nod1-dependent manner in response to microbial stimulation [ 22 , 23 ] . ecs have also been shown to express the nod2 receptor , which recognizes the bacterial peptidoglycan and muramyl dipeptide . moreover , ecs express a kind of pattern recognition receptors , such as cd36 scavenger receptor which bind to advanced glycation end - products . lps has been shown to modify native low density lipoprotein that can trigger tlr2 , tlr4 , and tlr6 signaling , thereby mediating the activation of inflammatory cells . for example , lps - induced ecs can produce il-1 , il-8 , and monocyte chemotactic protein-1 via tlr4 [ 2528 ] . these receptors induce a coordinated signaling network that ultimately activates nf-b and the subsequent production of chemoattractants , proinflammatory cytokines , and adhesion molecules . tlr3 , tlr7 , and tlr8 play an important role in detecting viral rna and activating innate immune responses against viruses , among which tlr3 has been reported expressed by ecs . interferon- ( ifn- ) is vital in regulating innate immunity against viruses and inducing tlr3 expression . in addition , ecs also express tlr9 that recognizes bacterial and viral dna   ( figure 1 ) . when innate immunity fails to eliminate inflammatory stimuli , the adaptive immune response will be triggered . ecs are involved in chronic inflammation by acting as antigen presenting cells ( apcs ) and via interactions with specialized effector cells . it has been confirmed that ecs express mhc i and mhc ii class molecules and process antigen to other cells in vitro . but both of them are still debatable in vivo . in addition , activated ecs also express costimulators including ox40 ligand , 4 - 1bb ligand , and inducible costimulator ligand , which are involved in formation , activation , and survival of memory t cell [ 32 , 33 ] . meanwhile , ecs treated with ifn- effectively induce cd4 + and cd8 + memory t cells to proliferate and produce cytokines . moreover , ecs also secrete cytokines which regulate and shape adaptive and innate immune responses to control the recruitment and influx of immune cells to sites of action . among these mediators between immune responses , the central cytokines are il-25 , il-33 , and thymic stromal lymphopoietin ( figure 1 ) . the inflammatory processes of ra and cvd are remarkably similar , suggesting that ra disease - related inflammation might contribute to the excess cvd risk . previous study suggested that ed may be related to increased cellular adhesion molecules , accumulation of reactive oxygen species , and changed production such like no [ 3638 ] . ed leads to a shift of ecs actions by various chemokines , cytokines , and other factors . the shift finally induces reduced vasodilation , proinflammatory state , and proliferative and prothrombotic properties . evidence suggests that coronary microvascular disease is apparent in the absence of macrovascular disease in ra . the synovium of ra patients has a pink or even red appearance due to the increased number of blood vessels . ecs eventually become vessels through primarily forming tubes together and move towards chemokine gradients through activation of chemokine receptors . chemokines of the cxc family are key mediators of angiogenesis in both physiological and pathological conditions . cxc chemokines are commonly classified into angiostatic chemokines ( inhibiting angiogenesis ) and angiogenic chemokines ( promoting angiogenesis ) , based on the presence of a tripeptide elr ( glu - leu - arg ) motif preceding the first conserved cysteine residue . all elr+ chemokines signal via c - x - c chemokine receptor 2 ( cxcr2 ) , but in humans chemokine ( c - x - c motif ) ligand 6 ( cxcl6 ) and cxcl8 also bind to cxcr1 . these two receptors are expressed by ecs and their ability to induce chemotaxis has been confirmed . however , cxcr2 is generally assumed as one of the major angiogenic receptors also in humans , since some ecs that express cxcr2 only can migrate in response to angiogenic chemokines . cxcr2 has been shown to bind to chemokine cxcl1 , cxcl2 , cxcl3 , cxcl5 , cxcl6 , cxcl7 , and cxcl8 . it has been reported that the inflammation of collagen - induced arthritis ( cia ) mice can also be improved through a peptide derived from the angiostatic chemokine cxcl4 . it has been demonstrated that the angiogenic activity of ra synovial tissue homogenate can be decreased by incubation with anti - cxcl8 antibodies . the exception currently known is cxcl12 , which lacks the elr motif and is expressed in ra fibroblast - like synoviocytes ( fls ) . cxcl12 , which usually combines with cxcr4 and cxcr7 , can inhibit the proangiogenic activity of elr+ chemokines and vascular endothelial growth factor ( vegf ) . as an instance of the thesis that cxcl12 and its receptor cxcr4 are involved in the formation of blood vessels in ra , angiogenic properties of ra synovial fluid were significantly decreased after incubation with anti - cxcl12 antibodies . cxcr7 has been reported to fail to support cxcl12 induced human endothelial progenitor cells ( epcs ) migration , proliferation , or no production but it mediated human epcs survival exclusively . in addition , the expression of cc chemokine ligand 28 and ccr10 is high in ra synovial tissue and can induce epc migration into ra joints   ( figure 2 ) . the cxc chemokines , cxcl4 , cxcl9 , cxcl10 , cxcl11 , cxcl4l1 , and the cc chemokine , ccl21 , activate cxcr3 , a cell - surface g protein - coupled receptor , which can be detected in ecs . the angiostatic functions of these chemokines depend on the capability of cxcr3 to inhibit the proliferation of ecs . cxcl4 is an inhibitor of ecs proliferation and migration either through interaction with cxcr3 or other ways [ 56 , 57 ] . these effects depend in part on their capability to block the binding of vegf to its receptors . unlike cxcl4 , cxcl4l1 ( nonallelic variant of cxcl4 ) induces chemokinesis of ecs but does not participate in ecs proliferation . however , the exact effect of these angiostatic chemokines on angiogenesis in ra is still unknown   ( figure 2 ) . it is known that inflammatory cytokines play a pivotal role in driving the disease process in ra . the cytokines synthesized by ecs that have been extensively studied are tnf- , il-1 , and il-6 [ 59 , 60 ] . tnf- has been studied for several years for its vital role in joint destruction and its control toward other proinflammatory cytokines . it also increases cellular infiltration in the synovium through enhancing chemokines expression , ecs activation , and angiogenesis . recent study specifically showed that il-17 had major procoagulant and prothrombotic effects on vessels when combined with tnf- . tnf- and il-1 both cause bone damage which is the hallmark of ra pathogenesis [ 62 , 63 ] . recent study found that tnf- and il-1 can increase the expression of grp78/bip , a representative er chaperone which has a high expression in ra synovium and fls . il-33 , as a member of il-1 family , is produced when ecs sense stimuli . il-33 is able to induce angiogenesis and ecs activation . in animal models of ra , il-1 works with il-6 during the early phases of disease , acting on ecs to secrete cytokines like il-8 and monocyte chemotactic protein 1 to attract monocytes . the joint destruction and disease progression of ra patients are related to high expression of il-6/sil-6r complex in synovial fluids . il-6 further upregulates chemokines that attract t cells , leading to enhanced cellular infiltration and beginning the transition from an acute inflammatory disease to ra . il-6 increases the concentration of vegf in ra fls to regulate vascular permeability , and increased permeability results in more inflammatory cells recruiting into the tissues and damage exacerbation . in addition , study demonstrated that the absence of il-6 induces complete protection against arthritis in cia mice and an anti - mouse il-6r monoclonal antibody inhibits development of arthritis in cia mice [ 69 , 70 ] . il-18 induces ecs migration and angiogenesis which contribute to sustain and develop the pannus formation . il-18 works through two ways among which are directly activating ecs and indirectly inducing ra fls to produce vegf and angiogenic chemokines . endocan or endothelial cell specific molecule-1 ( esm-1 ) is highly expressed in ra synovial tissue . the concentration of esm-1 is increased by il-1 , tnf- , and vegf and reduced by ifn- and il-4 . study demonstrated that endocan induced by adiponectin can stimulate cell invasion , cell migration , and angiogenesis in arthritic joints   ( figure 2 ) . vegf is able to induce the differentiation of ecs and ecs - driven angiogenesis in ra synovium . the vital molecule that controls inflammation - driven angiogenesis is vegf - a , a heparin - binding growth factor , inducing angiogenesis by acting on ecs , promoting cell mitogenesis , cell migration , and lumen formation [ 7176 ] . vegf - a signals induce angiogenesis via vascular endothelial cell receptor-1 ( vegfr-1 ) and vegfr-2 . cytokines , such as tnf- , can induce the combination of vegfr-2 and vegf - a , thereby resulting in angiogenesis at the site of inflammation [ 77 , 78 ] . vegf level was high in synovium , joint synovial fluid , and serum of patients with ra . up to now , a variety of cytokines have been shown to contribute to the formation of ra pannus , among which vegf is a vital cytokine that promotes the formation of pannus by specially acting on the ecs . demonstrated that serum vegf level and joint swelling , the disease activity score , the esr , and the crp of patients with early ra were positively correlated and proposed that vegf level may serve as an evaluation index for ra . in addition , vegf also plays a cooperative role with other factors such as tgf- , fgf , il-1 , and tnf- generated by vessels to promote pannus angiogenesis of ra . inversely , under the control of inflammatory cytokines in some ways , ecs itself also can secrete vegf to play a role in inflammation response . study recently demonstrated for the first time that tnf--induced b cell activating factor is able to regulate vegf - induced angiogenesis in ra through c - fos gene . ang ii is a cardiovascular mediator , for its primary role in the regulation of blood fluid homeostasis and blood pressure . as a vasoconstrictor study has reported that ang ii can induce ed , vascular hypertrophy , and hypertensive response in adjuvant arthritis ( aa ) rat model [ 83 , 84 ] . it also has a direct influence on the progression of the atherosclerotic process via effects on endothelial function , inflammation , fibrinolytic balance , and plaque stability . ang ii has two major receptor subtypes , the ang ii type 1 receptor ( at1r ) and ang ii type 2 receptor ( at2r ) . at1r and at2r , expressed in most organs and tissues , for example , it has been previously reported that the at1r is present and upregulated in the synovium of ra patients [ 87 , 88 ] . in addition , at1r blockers are known to have direct or indirect anti - inflammatory actions . ed in the circumstance of cvd is partly dependent on the production of reactive oxygen species ( ros ) . at1r - induced ros not only destroys no but also reduces no formation in the endothelium . kawakami et al . have demonstrated that at1r and at2r are expressed in articular chondrocytes of ra patients . the at2 receptor antagonises many effects of the at1 receptor , for example , cell proliferation . however , it is still debatable in the functions of at2r ; the majority support the concept that the at2r has antifibrotic , antiproliferative , and anti - inflammatory effects [ 93 , 94 ] . increased cardiovascular morbidity and mortality in ra patients have been widely reported . however , to date , drugs treating ra are primarily aimed at prevention of swelling and pain and inhibition of bone erosions . for example , classical nonsteroidal anti - inflammatory drugs and new selective inhibitors of cyclooxygenase-2 have been successfully used for several decades in the treatment of ra patients . however , in recent years , these drugs have been recognized to increase cardiovascular risk . this risk exists and can be explained by a blood pressure increasing effect and the development of ed . therefore , drugs effectively improve ed in ra patients which may be a potential way used in monotherapy or drug combination as an assist . methotrexate ( mtx ) , a gold standard drug in the treatment of ra , has been shown to inhibit angiogenesis and suppresses the expression of e - selectin and icam-1 from dermal ecs . recently , shaker et al . also demonstrated that mtx cause reduction in the amount of vegf expression via an antiangiogenesis mechanism . moreover , other study reported that mtx therapeutically conditions vascular endothelium via activation of ampk - creb for example , etanercept induced a significant decrease in left ventricular mass index ( a strong marker of cardiovascular mortality and vessel abnormalities ) with medium - term treatment . the disease activity of circulating epcs can proportionally reduce by a short - term treatment with tnf- inhibitor . study reported that avastin can decrease the arthritis index , target - to - nontarget ratio , and synovial pathological injury index of type ii collagen - induced arthritis rats . similarly , bevacizumab , as the first antibody for vegf , has shown initial preclinical and clinical activity in treating ra . schulz et al . demonstrated for the first time that , in aa rat model , losartan , an at1r inhibitor , remarkably reversed the relaxation of ecs - derived hyperpolarizing factor that is damaged . similarly , at1r inhibitor , irbesartan , has been demonstrated to be able to improve ed in antigen - induced arthritis . generally , these findings reveal that at1r is a potential target to treat ed and may through this way exert its therapeutic effect . evidence has indicated the important role of ed in increased cardiovascular risk in ra patients . on the one hand , drugs targeting ed are of interest from the dual perspectives of disease modification and cardiovascular risk reduction when applied to monotherapy . on the other hand , these drugs may at least act as effective adjunctive therapy in drug combination for disease control in ra patients . however , there are still many gaps in our knowledge regarding these potentially ecs . this will still require a uniform approach of experimental studies in humans and nonhuman models . specifically in patients with ra , it remains to be determined whether simple control of inflammation will be sufficient to restore ecs function .
inflammation , as a feature of rheumatoid arthritis ( ra ) , leads to the activation of endothelial cells ( ecs ) . 
 activated ecs induce atherosclerosis through an increased expression of leukocyte adhesion molecules . 
 endothelial dysfunction ( ed ) is recognized as a failure of endothelial repair mechanisms . 
 it is also an early preclinical marker of atherosclerosis and is commonly found in ra patients . 
 ra is now established as an independent cardiovascular risk factor , while mechanistic determinants of ed in ra are still poorly understood . 
 an expanding body of study has shown that ec at a site of ra is both active participant and regulator of inflammatory process . over the last decade , 
 a role for endothelial dysfunction in ra associated with cardiovascular disease ( cvd ) has been hypothesized . at the same time , several maintenance drugs targeting this phenomenon have been tested , which has promising results . 
 assessment of endothelial function may be a useful tool to identify and monitor ra patients .