Vascular involvement in rheumatic diseases: 'vascular rheumatology'
© BioMed Central Ltd 2008
Published: 10 October 2008
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© BioMed Central Ltd 2008
Published: 10 October 2008
The vasculature plays a crucial role in inflammation, angiogenesis, and atherosclerosis associated with the pathogenesis of inflammatory rheumatic diseases, hence the term 'vascular rheumatology'. The endothelium lining the blood vessels becomes activated during the inflammatory process, resulting in the production of several mediators, the expression of endothelial adhesion molecules, and increased vascular permeability (leakage). All of this enables the extravasation of inflammatory cells into the interstitial matrix. The endothelial adhesion and transendothelial migration of leukocytes is a well-regulated sequence of events that involves many adhesion molecules and chemokines. Primarily selectins, integrins, and members of the immunoglobulin family of adhesion receptors are involved in leukocyte 'tethering', 'rolling', activation, and transmigration. There is a perpetuation of angiogenesis, the formation of new capillaries from pre-existing vessels, as well as that of vasculogenesis, the generation of new blood vessels in arthritis and connective tissue diseases. Several soluble and cell-bound angiogenic mediators produced mainly by monocytes/macrophages and endothelial cells stimulate neovascularization. On the other hand, endogenous angiogenesis inhibitors and exogenously administered angiostatic compounds may downregulate the process of capillary formation. Rheumatoid arthritis as well as systemic lupus erythematosus, scleroderma, the antiphospholipid syndrome, and systemic vasculitides have been associated with accelerated atherosclerosis and high cardiovascular risk leading to increased mortality. Apart from traditional risk factors such as smoking, obesity, hypertension, dyslipidemia, and diabetes, inflammatory risk factors, including C-reactive protein, homocysteine, folate deficiency, lipoprotein (a), anti-phospholipid antibodies, antibodies to oxidized low-density lipoprotein, and heat shock proteins, are all involved in atherosclerosis underlying inflammatory rheumatic diseases. Targeting of adhesion molecules, chemokines, and angiogenesis by administering nonspecific immunosuppressive drugs as well as monoclonal antibodies or small molecular compounds inhibiting the action of a single mediator may control inflammation and prevent tissue destruction. Vasoprotective agents may help to prevent premature atherosclerosis and cardiovascular disease.
Vessels and the vascular endothelium are involved in the pathogenesis of inflammatory rheumatic diseases. Rheumatoid arthritis (RA) serves as a prototype of these diseases as it is the most common type of arthritis and a great body of data is available regarding leukocyte recruitment into the synovium, angiogenesis, and accelerated atherosclerosis. The term 'vascular rheumatology' has been accepted by many investigators and includes both microvascular and macrovascular involvement in rheumatic diseases. Apart from RA, systemic lupus erythematosus (SLE), systemic sclerosis (SSc), the antiphospholipid syndrome (APS), and systemic vasculitides have been associated with vascular inflammation, altered angiogenesis, and increased cardiovascular morbidity and mortality. In this review, we will discuss the most relevant information on arthritis-related vascular inflammation, including the role of endothelial cells (ECs), endothelial adhesion molecules (CAMs) and chemokines, as well as the involvement of neovascularization and some aspects of accelerated atherosclerosis in rheumatic diseases. We will discuss RA in more detail, and other connective tissue diseases described above will also be mentioned. Finally, some aspects of vascular targeting in rheumatology will also be briefly summarized.
Some important inflammatory mediators released by vascular endothelial cells
Monocyte chemoattractant protein-1/CCL2
Endothelial cell-derived growth factor
Transforming growth factor-beta
Granulocyte colony-stimulating factor
Granulocyte-macrophage colony-stimulating factor
Relevant members of the selectin, integrin, and immunoglobulin adhesion molecule superfamilies
L-selectin (CD62L, LAM-1)
Sialylated carbohydrates, GlyCAM-1
E-selectin (CD62E, ELAM-1)
P-selectin (CD62P, PADGEM)
Sialyl-Lewis-X, other carbohydrates
Laminin, collagen, fibronectin
ICAM-1, ICAM-2, ICAM-3, JAM-A
Vitronectin, von Willebrand factor, other matrix molecules
αLβ2 (LFA-1), αMβ2 (Mac-1, CR3)
PECAM-1, αVβ3 integrin
Chemokine receptors with ligands relevant for arthritis and angiogenesis
CXC chemokine receptors
IL-8/CXCL8, ENA-78/CXCL5, groα/CXCL1, CTAP-III/CXCL7
IP-10/CXCL10, PF4/CXCL4, Mig/CXCL9, ITAC/CXCL11
C-C chemokine receptors
MIP-1α/CCL3, RANTES/CCL5, MCP-3/CCL7, MPIF-1/CCL23
C chemokine receptors
C-X3-C chemokine receptors
Fractalkine/CX3CL1 has also been detected in RA synovial tissues . Fractalkine/CX3CL1 has also been implicated in the development of accelerated atherosclerosis , a topic discussed later. Chemokines bind to their seven-transmembrane domain receptors expressed on the target cells [12, 18]. Some of these receptors have numerous chemokine ligands whereas others are specific receptors for single ligands . Chemokine receptors have also been associated with various histological subtypes of inflammation. For example, whereas CXCR3 and CCR5 may be involved primarily in Th1 type diseases (such as RA), CCR3, CCR4, and CCR8 may play a role in leukocyte migration underlying Th2 type inflammation (such as asthma) . Most CXC and CC chemokine receptors mentioned above as well as XCR1 and CX3CR1 are expressed in the arthritic synovium [14, 17, 18].
Leukocyte adhesion to ECs occurs following a cascade of events. White blood cells in the bloodstream weakly adhere to the endothelium lining the inner vessel wall (tethering) followed by rolling of leukocytes on the endothelial layer. Tethering and rolling are mediated primarily by selectins and their ligands. These events are followed by leukocyte activation, which is dependent upon interactions between chemokine receptors expressed on leukocytes and proteoglycans on ECs. Activation-dependent firm adhesion occurs next, involving α4β1 integrin/VCAM-1 (vascular cell adhesion molecule-1), β2 integrin/ICAM-1, and JAM/integrin interactions. This is associated with the secretion of chemokines. These chemokines may also upregulate integrin expression on the adhering cells via PI3K (phosphatidylinositol 3-kinase)- mediated pathways. Leukocyte diapedesis through the endothelial layer involving integrins occurs when chemokines bind to endothelial heparan sulphate. Chemokines preferentially chemoattract EC-adherent leukocytes. These processes lead to the transmigration of leukocytes into the inflamed tissue [1, 8].
Inhibition of cell adhesion, chemokines, and migration using specific antibodies or purified ligands has provided an important perspective on the molecular pathogenesis of RA. In addition, some of these strategies may be included in the future therapy of arthritis . Regarding anti-CAM trials, an anti-human ICAM-1 antibody (enlimomab) was tried in refractory RA with little success [2, 20]. Other antiadhesion strategies have been introduced into the treatment of other inflammatory diseases. For example, efalizumab (anti-LFA-1) and alefacept (LFA-3-Ig fusion protein) have been tried in psoriasis, natalizumab (anti-α4 integrin) in multiple sclerosis and Crohn disease, and an anti-α4β7 integrin monoclonal antibody in ulcerative colitis [2, 3, 20]. These and other anti-CAM strategies may be tried in arthritis as well [2, 3, 20]. Chemokines and chemokine receptors can be targeted in a number of ways. Disease-modifying antirheumatic drugs (DMARDs) and anti-TNF biologics, currently used in the treatment of RA, may indirectly influence chemokine production . Antibodies to IL-8/CXCL8, ENA-78/CXCL5, CXCL16, MIP-1α/CCL3, MCP-1/CCL2, and fractalkine/CX3CL1 have been used to control arthritis in various rodent models [18–20]. Several oral chemokine receptor antagonists, including CXCR2, CXCR4, CCR1, CCR2, and CCR5 inhibitors, have been tried in human RA as well as in animal models of arthritis [18, 20–22].
Some angiogenic and angiostatic factors in arthritis
IL-8/CXCL8, ENA-78/CXCL5, groα/CXCL1, CTAP-III/CXCL7, SDF-1/CXCL12, MCP-1/CCL2, SLC/CCL21, MPIF/CCL23, fractalkine/CX3CL1
PF4/CXCL4, IP-10/CXCL10, Mig/CXCL9, SLC/CCL21
Type I collagen, fibronectin, laminin, heparin, heparan sulphate
Thrombospondin, RGD sequence
Cell adhesion molecules
β1 and β3 integrins, E-selectin, P-selectin, CD34, VCAM-1, endoglin, PECAM-1, vascular endothelial-cadherin, Lewisy/H, MUC18
RGD sequence (integrin ligand)
VEGF, bFGF, aFGF, PDGF, EGF, IGF-I, HIF-1, TGF-βa
TNF-α, IL-6a, IL-15, IL-18
IL-4, IL-6a, IFN-α, IFN-γ
MMPs, plasminogen activators
TIMPs, plasminogen activator inhibitors
Angiogenin, substance P, prolactin
DMARDs, infliximab, etanercept, angiostatin, endostatin
The major chemoattractant that drives EPCs is the SDF-1/CXCL12 chemokine and its receptor, CXCR4 . In arthritis, proinflammatory cytokines stimulate the production of SDF-1/CXCL12 and thus tissue vasculogenesis by recruiting CXCR4+ EPCs [14, 17, 29].
The hypoxia-VEGF-angiopoietin pathway is an essential angiogenic network in synovitis [16, 23–25, 30]. VEGF, a growth factor that binds to heparin in the synovial ECM, plays a central role in the regulation of neovascularization [23, 30]. There is hypoxia present within the joint cavity, and hypoxia as well as TNF-α and IL-1 stimulate VEGF release . Hypoxia acts through the hypoxia-inducible factor heterodimer, HIF-1α/HIF-1β . Several other angiogenic mediators also act indirectly via VEGF . Angiopoietin-1 (Ang1) and Ang2 regulate EC functions upon stimulation by VEGF. Both Ang1 and Ang2 interact with the Tie2 endothelial tyrosine kinase receptor [16, 24]. Ang1-Tie2 interactions result in vessel stabilization. On the other hand, Ang2, an antagonist of Ang1, inhibits vessel maturation . Another important player in this network is survivin, an apoptosis inhibitor, which is also involved in VEGF-induced angiogenesis and EC survival . VEGF, HIF-1, Ang1, Tie2, and survivin are all expressed in the arthritic synovium [16, 25]. Growth factors other than VEGF but implicated in angiogenesis include fibroblast (FGF-1 and FGF-2), hepatocyte, platelet-derived, epidermal (EGF), insulin-like, and transforming (TGF-β) growth factors [16, 24, 25]. Among chemokines described above, CXC chemokines that contain the ELR (glutamic acid-leucine-arginine) amino acid motif promote angiogenesis . ELR+CXC chemokines that stimulate angiogenesis and also synovial inflammation include IL-8/CXCL8, ENA-78/CXCL5, groα/CXCL1, and CTAP-III/CXCL7. SDF-1/CXCL12 is a unique CXC chemokine as it exerts mainly a homeostatic function, yet it has been implicated in inflammation such as in RA [13, 14, 17, 29]. Moreover, this chemokine lacks the ELR motif but is still angiogenic [14, 29]. The crucial role of SDF-1/CXCL12 in vasculogenesis is discussed above . In contrast to angiogenic CXC chemokines, the ELR-PF4/CXCL4, IP-10/CXCL10, and Mig/CXCL9 suppress neovascularization [13, 14, 17]. Regarding CC chemokines, MCP-1/CCL2 promotes neovascularization induced by growth factors [14, 17]. The sole CX3C chemokine, fractalkine/CX3CL1, also promotes synovial angiogenesis [14, 17, 19]. Regarding chemokine receptors, CXCR2, which binds most ELR+ CXC chemokines described above, is a crucial chemokine receptor in angiogenesis [13, 14, 17]. CXCR4 has been implicated in SDF-1/CXCL12-induced neovascularization in arthritis [14, 17, 29]. In contrast, CXCR3, a receptor for the angiostatic IP-10/CXCL10 and Mig/CXCL9, may be involved in chemokine-mediated angiostasis [14, 17]. Numerous proinflammatory cytokines, such as TNF-α, IL-1, IL-6, IL-15, IL-17, IL-18, granulocyte and granulocyte-macrophage colony-stimulating factors, oncostatin M, and macrophage migration inhibitory factor, also induce synovial angiogenesis [16, 31]. In contrast, other cytokines, such as IFN-α, IFN-γ, IL-4, IL-12, IL-13, and leukemia inhibitory factor, suppress the production of angiogenic mediators and thus inhibit neovascularization [16, 31, 32]. ECM components, matrix-degrading proteases, and cellular adhesion molecules described above may be involved in EC emigration, sprouting, and thus angiogenesis. Among ECM components, various types of collagen, fibronectin, laminin, vitronectin, tenascin, and proteoglycans promote neovascularization . Proteolytic enzymes, such as MMPs and plasminogen activators, play a role in matrix degradation underlying synovial angiogenesis [16, 25]. On the other hand, tissue inhibitors of metallo-proteinases and plasminogen activator inhibitors antagonize the angiogenic effects of proteases described above [16, 32]. Among CAMs, β1 and β3 integrins, E-selectin, glycoconjugates (including Lewisy/H), melanoma cell adhesion molecule (MUC18), VCAM-1, PECAM-1, and endoglin have been implicated in neovascularization [2, 16, 25, 33, 34]. The αVδ3 integrin is of outstanding importance as this CAM mediates both synovial angiogenesis and osteoclast-mediated bone resorption and the development of erosions in RA . Other important angiogenic factors not mentioned above include endothelin-1, angiogenin, angiotropin, and many others [16, 25] (Table 4). Angiostatic mediators and compounds also include angiostatin (a fragment of plasminogen), endostatin (a fragment of type XIII collagen), thrombospondin-1, 2-methoxyestradiol, paclitaxel, osteonectin, chondromodulin-1, and others [16, 30, 32, 35] (Table 4). These molecules suppress the action of angiogenic mediators, such as VEGF, HIFs, or the αVβ3 integrin [16, 30, 32, 35].
Differential vascular morphology may exist in the synovia of RA versus psoriatic arthritis (PsA) patients [16, 25]. Furthermore, VEGF production may be associated with increased disease activity and accelerated angiogenesis in PsA and ankylosing spondylitis . In SLE, angiogenic EGF, FGF, and IL-18 as well as angiostatic endostatin have been detected in the sera of patients. Serum VEGF levels were correlated with the SLAM (systemic lupus activity measure) activity score [16, 25]. Angiogenesis in SSc is somewhat controversial. On one hand, there is significant loss of vessels in scleroderma despite severe tissue hypoxia associated with increased concentrations of the angiostatic endostatin [16, 28]. On the other hand, SSc skin biopsy explants stimulated neovascularization and there is increased production of VEGF in the sera and skin of scleroderma patients [16, 28]. Thus, hypoxia may induce angiogenesis in SSc but this is transient and the newly formed vessels are rather unstable in this disease . Furthermore, sustained production of VEGF results in the formation of giant capillaries seen using capillaroscopy in SSc [16, 28]. Similarly to SSc, in inflammatory myopathies, expression of hypoxia-associated increased HIF-1, αVβ3 integrin, and VEGF receptor in muscle biopsies was not sufficient to compensate the loss of blood vessels [16, 25]. Regarding systemic vasculitides, abundant production of angiogenic VEGF and TGF-β has been associated with Kawasaki syndrome . Increased serum levels of TGF-β were found in ANCA (antineutrophil cytoplasmic antibody)-associated vaculitides, including Wegener granulomatosis, Churg-Strauss syndrome, and microscopic polyangiitis [16, 25].
Platelet factor-4/CXCL4 chemokine
Classical disease-modifying antirheumatic drugs
Anti-tumor necrosis factor biologics
Vascular endothelial growth factor inhibitors
Hypoxia-inducible factor heterodimer inhibitors
αVβ3 integrin inhibitors
Microtubule destabilizers (for example, paclitaxel)
Others (for example, glitazones)
Common risk factors in the pathogenesis of atherosclerosis underlying rheumatic diseases
Acute-phase proteins (C-reactive protein, fibrinogen)
Folate and vitamin B12 deficiency
Decreased paraoxonase activity
CD4+/CD28- T cells
Autoantibodies (anti-CCP, rheumatoid factor, anti-oxLDL, anti-phospholipid antibody, anti-hsp)
Proatherogenic cytokines (tumor necrosis factor-alpha, interleukin-6)
Angiogenic growth factors
Increased cell adhesion molecule expression
Methotrexate – bimodal?
Corticosteroids – bimodal?
Indeed, several inflammatory and atherogenic mediators, including homocysteine, lipoprotein (a), C-reactive protein (CRP), hyperhomocysteinemia, and folate, and vitamin B12 deficiency and decreased paraoxonase-1 activity are strongly associated with atherosclerosis and CVD [36, 42, 43]. Athero-sclerotic plaques, similarly to the RA joint, are characterized by enhanced accumulation of inflammatory monocytes/macrophages and T cells. These inflammatory leukocytes abundantly produce proinflammatory cytokines, chemokines, and MMPs [42, 43]. CD4+ T cells, especially the CD4+/CD28- T-cell subset, have been associated with both arthritis and inflammation-related vascular damage [37, 38, 43]. Regarding proinflammatory cytokines, TNF-α and IL-6 play an important role in atherosclerosis as well as in RA [31, 36, 43]. Increased production of TNF-α and IL-6 has been associated with heart failure as well as with insulin resistance, dys-lipidemia, and obesity [36, 43]. In contrast, IL-4 and IL-10 may exert an anti-inflammatory role during the development of atherosclerosis by driving Th2 responses [31, 43] (Table 6).
In RA, age, gender, ethnicity, traditional risk factors described above as well as (among RA-related risk factors) disease duration, activity, and severity, functional impairment, rheumatoid factor and anti-CCP status, CRP, radiographic indicators, presence of the shared epitope, and treatment modalities have been implicated in the development of accelerated atherosclerosis [36–38, 44]. We have recently assessed common carotid intima-media thickness (ccIMT) indicating atherosclerosis and flow-mediated vasodilation (FMD), a marker of endothelial dysfunction in RA. Increased ccIMT and impaired FMD have been associated with age, disease duration, and anti-CCP, CRP, and IL-6 production . In SLE, primary APS (PAPS) and secondary APS associated with SLE, traditional, and autoimmune-inflammatory factors are involved . Among these factors, longer disease duration and cumulative corticosteroid dose seem to
be the major predictors of clinical atherosclerosis [37, 38, 40, 41]. Additional inflammatory risk factors include CRP, fibrinogen, IL-6, costimulatory molecules (CD40/CD40L), CAMs, anti-phospholipid antibodies (APAs), including anti-cardiolipin and anti-β2 glycoprotein I (anti-β2GPI), anti-oxidized low-density lipoprotein (anti-oxLDL), anti-oxidized palmitoyl arachidonoyl phosphocholine (anti-oxPAPC), anti-HDL and anti-hsp antibodies, homocysteine, and lipoprotein (a) [37, 40, 41]. APAs are of importance in both SLE and APS. APAs may bind to neoepitopes of oxLDL as well as to oxLDL-
β2GPI complexes, and both APA and anti-oxLDL antibodies have been implicated in the pathogenesis of atherosclerosis associated with SLE and APS [37, 38, 40, 41]. Autoantibodies against oxLDL-β2GPI complexes have been detected in SLE and PAPS patients [40, 41]. Both APA and anti-oxLDL may account for increased mortality in CVD . The β2GPI phospholipid cofactor has been detected in the wall of large arteries in the vicinity of CD4+ T-cell infiltrates. Macrophages and ECs bind to β2GPI during the atherosclerotic process [37, 38, 41]. Atherosclerosis is the most pronounced in lupus-associated secondary APS, in which traditional and nontraditional risk factors are multiplied and atherosclerosis occurs more prematurely [40, 41]. SSc is associated with both macrovascular disease (including CVD, pulmonary hypertension, and peripheral arterial occlusion) and micro-vascular disease (including Raynaud phenomenon) [37–39, 45, 46]. Pathogenic factors involved in SSc-associated vascular damage include increased LDL, homocysteine, and CRP production [37, 39, 46]. We recently described the association of 5,10-methylene-tetrahydrofolate reductase (MTHFR) C677T polymorphism with homocysteine, vitamin B12 production, and macrovascular abnormalities in SSc . Increased arterial stiffness and ccIMT as well as impaired FMD have been detected by us [39, 45] and others  in scleroderma.
Anti-inflammatory treatment used in inflammatory rheumatic diseases may be either proatherogenic or antiatherogenic [37, 47]. Corticosteroids are atherogenic by augmenting dys-lipidemia, hypertension, and diabetes mellitus [36, 47]. In autopsy studies, long exposure to corticosteroid therapy was associated with the development of atherosclerosis. However, other clinical studies could not confirm this association [36, 47]. Glucocorticoids may exert a bimodal action as they are atherogenic but, on the other hand, also anti-inflammatory. There is evidence that the above-described inflammatory factors associated with more active disease may exert higher risk for atherosclerosis than anti-inflammatory treatment [37, 47]. In contrast to corticosteroids, antimalarial drugs such as chloroquine and hydroxychloroquine may exert evident antiatherogenic properties. Antimalarials may reduce LDL cholesterol, very LDL cholesterol, and (in corticosteroid-treated patients) triglyceride production [36, 37, 47]. Methotrexate (MTX) exerts bipolar effects on atherosclerosis in RA: on one hand, MTX treatment increases plasma levels of homocysteine, but, on the other hand, MTX controls several other mediators of inflammation and thus may beneficially influence the net outcome of CVD in RA [36, 47]. Concomitant folate supplementation prevented the increase of homocysteine production and reduced CVD mortality in MTX-treated patients . Among biologic agents, TNF-α blockers may have significant effects on the vasculature . In RA, infliximab treatment reduced endothelial dysfunction and ccIMT . We recently proposed that rituximab may also exert favorable effects on FMD, ccIMT, and dyslipidemia . Atherosclerosis treatment strategies in rheumatic diseases should include an aggressive control of all traditional risk factors, including hyperlipidemia, hypertension, smoking, obesity, and diabetes mellitus. Both pharmacological treatment and changes in lifestyle should be introduced in these patients . There is very little solid evidence from randomized controlled trials indicating the preventative action of any drugs in arthritis-associated CVD . Drug therapy may include the use of antiplatelet agents, statins, folic acid, B vitamins, and (as described above) possibly antimalarials [36, 47]. A recommendation from the European League Against Rheumatism for the prevention and management of CVD in arthritis is about to be published .
In this review, we discussed the putative role of leukocyte-EC adhesion, chemokines, and angiogenesis in leukocyte recruitment underlying the pathogenesis of inflammatory synovitis. A number of CAMs are involved in this process. These CAMs interact with soluble inflammatory mediators such as cytokines and chemokines. The presence of various CAM pairs and the existence of distinct steps of rolling, activation, adhesion, and migration account for the diversity and specificity of leukocyte-EC interactions. Chemokines and their receptors drive inflammatory leukocytes into the synovium. A number of soluble and cell-bound factors may stimulate or inhibit angiogenesis. The outcome of inflammatory and other 'angiogenic diseases' such as various forms of arthritis depends on the imbalance between angiogenic and angiostatic mediators. There have been several attempts to therapeutically interfere with the cellular and molecular mechanisms described above. Specific targeting of leukocyte adhesion, CAMs, chemokines, chemokine receptors, and/or angiogenesis, primarily by using agents with multiple actions, may be useful for the future management of inflammatory rheumatic diseases.
β2 glycoprotein I
anti-endothelial cell antibody
anti-cyclic citrullinated peptide
anti-oxidized low-density lipoprotein
endothelial adhesion molecule
common carotid intima-media thickness
connective tissue-activating peptide-III
disease-modifying antirheumatic drug
epidermal growth factor
epithelial neutrophil-activating protein-78
endothelial progenitor cell
fibroblast growth factor
high endothelial venule
intercellular adhesion molecule
interferon-gamma-inducible 10-kDa protein
junctional adhesion molecule
lymphocyte function-associated antigen
monocyte chemoattractant protein-1
monokine induced by interferon-gamma
macrophage inflammatory protein-1-alpha
oxidized low-density lipoprotein
primary antiphospholipid syndrome
platelet-endothelial cell adhesion molecule-1
stromal cell-derived factor-1
systemic lupus erythematosus
transforming growth factor-beta
tumor necrosis factor
vascular cell adhesion molecule
vascular endothelial growth factor
This work was supported by National Institutes of Health (Bethesda, MD, USA) grants AR-048267 and AI-40987 (AEK), the William D Robinson, MD, and Frederick GL Huetwell Endowed Professorship (AEK), funds from the Veterans' Administration (AEK), and grant T048541 from the National Scientific Research Fund (OTKA) (ZS).