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Review in vasculitides N. Maruotti1, F.P. Cantatore1, B. Nico2, A. Vacca3, D. Ribatti2

1Department of Rheumatology, University ABSTRACT angiogenic and anti-angiogenic fac- of Foggia Medical School, Foggia, Italy; Vasculitides, including Wegener’s ggran-ran- tors (2) (Table I). Vascular endothelial 2 Department of Human Anatomy and ulomatosis, Takayasu’s ,arteritis, ggiantiant growth factor (VEGF) family members, Histology and 3Department of Biomedical arteritis, Kawasaki disease, Behçet fi broblast growth factor (FGF) family Sciences and Clinical Oncology, University of Bari Medical School, Bari, disease, thromboangiitis obliterans members, -derived growth fac- Italy. and erythema elevatum diutinum, are tor (PDGF), transforming growth factor Nicola Maruotti, Francesco P. Cantatore, infl ammatory diseases of vessel alpha and beta (TGF-α and β), tumor Beatrice Nico, Angelo Vacca, Domenico wall characterized by myointimal pro- necrosis factor alpha (TNF-α), inter- Ribatti. liferation, fi brosis and thrombus forma- leukins (IL), chemokines, , This study was supported by the tion leading to stenosis or occlusion of and have a positive regu- Associazione Italiana per la Ricerca sul the vascular lumen, and fi nally to tissue latory activity. On the contrary, angio- Cancro (AIRC, National and Regional ischemia. In these diseases the hypoxic statin, , and thrombospon- Funds) Milan, Ministry for Education, environment subsequent to stenosis or din have a negative regulatory activity the Universities and Research (Project occlusion of the vascular lumen is a (3-5). The net balance between these CARSO n. 72/2; FIRB 2001 and PRIN potent signal for the generation of new 2005), Rome, and Fondazione Italiana per positive and negative factors, with a la Lotta al Neuroblastoma, Genoa, Italy. blood vessels. Angiogenesis may be a prevalence of positive regulators, or Please address correspondence to: compensatory response to ischemia a downregulation of the expression of Prof. Domenico Ribatti, Department and to the increased metabolic activity negative regulators, is responsible for of Human Anatomy and Histology, and may be also a further infl amma- inducing and regulating the angiogenic Policlinico, Piazza Giulio Cesare 11, tory stimulus because endothelial cells process (2) (Fig. 1). I-70124 Bari, Italy. of newly-formed vessels express adhe- E-mail: [email protected] sion molecules and produce colony- Angiogenesis in chronic Received on June 18, 2007; accepted in stimulating factors and chemokines for infl ammation revised form on October 2, 2007. leukocytes. Angiogenesis plays a key role in the Clin Exp Rheumatol 2008; 26; 476-483. pathogenic events leading to chronic © CopyrightCopyright CLINICAL AND Angiogenesis infl ammation. Chronic infl ammatory EXPERIMENTAL RHEUMATOLOGY 2008.2008. Angiogenesis is the formation of newly- lesions occuring in several diseases, formed capillaries from pre-existing such as rheumatoid arthritis, Crohn’s Key words: Angiogenesis, vessels. It is characterized by a well- disease, ulcerative colitis, primary bil- infl ammation, vasculitides. programmed cascade of events which iary cirrhosis, and vasculitides (6-10) contains a number of distinct steps (1). are characterized by cellular infi ltrates Angiogenic factors activate endothelial and newly-formed vessels involved in cells, inducing them to produce, in turn, favouring infl ammatory cells recruit- proteolytic enzymes such as matrix ment and providing a compensatory re- and plasminogen sponse to ischemia and to the increased activators, which are responsible of the metabolic activity (11, 12). degradation of the basement membrane Angiogenic factors induce endothelial and of the perivacular extracellular ma- cells to express adhesion molecules, trix. The proliferation and migration of and chemokines, which endothelial cells into the perivascular may have additive stimulatory ef- area and the subsequent lumenation fects on chronic infl ammation. VEGF of these “primary sprouts” forming promotes the migration of infl amma- “capillary loops” and the synthesis of tory cells, such as and lym- new basement membrane, lead fi nally phocytes, into the extracellular matrix to new vessel formation. Endothelial via inducing vascular permeability and cells of the “primary sprouts” prolifer- endothelial cells expression of adhe- ate and migrate to generate secondary sion molecules, such as VCAM-1 and and further generations of sprouts. ICAM-1 (13, 14). FGF-1 and FGF-2 Competing interests: none declared. Angiogenesis is regulated by several promote endothelial cell production of

476 Angiogenesis in vasculitides / N. Maruotti et al. REVIEW

Table I. Main angiogenic and anti-angiogenic factors that regulate angiogenesis. At the present time, the Chapell Hill Consensus Conference Nomenclature Angiogenic factors* Angiogenic activity of primary vasculitides (Table II) pro- In vitro assays In vivo assays vide a useful guide to clinician and pa- Proliferation Migration Capillary tube thologist for evaluating a patient with a fromation idiopathic form of . This clas- sifi cation is based on the predominant Vascular endothelial growth factor (VEGF) S S S S Fibroblast growth factor-2 (FGF-2) S S S S size of vessels affected and describes Platelet derived growth factor (PDGF) N S = S the main clinico-pathologic features of Transforming growth factors beta (TGF-β) I N S S the various clearly defi ned types of sys- -1 N S S S temic vasculitis. Anti-angiogenic factors* Vasculitides are also classifi ed on the -1 I I I I basis of their histopathologic features Angiostatin I I I I into neutrophilic or leukocytoclastic Endostatin I I I I vasculitis, lymphocytic vasculitis, and *All the angiogenic and the anti-angiogenic factors may be considered as pleiotropic growth factors, granulomatous vasculitis (20). Leuko- which recognize several producing and effector cells, such as endothelial cells, pericytes, infl ammatory cytoclastic vasculitis is an infl amma- cells and tumor cells. tion of small-vessel characterized by I: inhibition; N: no effect; S: stimulation; =: no fi ndings available. segmental angiocentric neutrophilic infl ammation, endothelial cell dam- age and fi brinoid necrosis. These his- topathologic features may be found in cryoglobulinemia and rarely in multiple myeloma (21). Lymphocytic vasculitis, characterized by lymphocytic recruit- ment of infl ammatory cells and cyto- toxic reactions, is the histopathologic pattern of lymphocytic endovasculitis, lymphocytic lichenoid vasculitis and granulomatous vasculitis (22). Granu- lomatous vasculitis is a granulomatous infl ammation with extensive necrosis and a variegated cellular infi ltrate. We- gener’s granulomatosis is an example of this histopathologic pattern (23). These disorders are characterized by infl ammation of blood vessel wall. The fi nal result is myointimal prolifera- Fig. 1. Angiogenesis results from the balance between pro- and anti-angiogenic factors. tion, fi brosis and thrombus formation leading to stenosis or occlusion of the plasminogen activator and collagenase Vasculitides vascular lumen, and fi nally to tissue which allow the migration of infl amma- Vasculitides are an heterogenous group ischemia (24). Even if aetiology of vas- tory cells via degradation of the extra- of disorders including giant cell arteri- culitides is still unknown, , cellular matrix (15). Other angiogenic tis, Takayasu’s arteritis, Cogan’s syn- infl ammatory disorders, autoimmuni- factors involved in infl ammatory cells drome, Behçet disease, polyarteritis tary disorders and drugs are involved recruitment are chemokines containing nodosa, thromboangiitis obliterans, Ka- as triggers for disease activity in vas- the ELR motif (glutamyl-leucyl-argi- wasaki disease, primary angiitis of the culitides (25-27). nyl sequence), such as CXC chemok- central nervous system, Goodpasture’s Because the etiologies of most from of ines (16, 17). disease, cutaneous leukocytoclastic vasculitis remain unknown, the most Most angiogenic factors, such as TNF-α, angitiis, Henoch-Schönlein purpura, valid basis for classifying the vascu- IL-1, IL-6, IL-8, and IL-18 are also in- hypocomplementemic urticarial vascu- litides is the size of the predominant fl ammatory factors involved in increas- litis, essential cryoglobulinemia, ery- blood vessels involved. Large vessel ing the production of other infl amma- thema elevatum diutinum, Wegener’s vasculitis involves the aorta and its ma- tory cytokines and cell adhesion mol- granulomatosis, microscopic polyangii- jor branches; medium vessel vasculitis ecules, and in enhancing matrix metal- tis, Churg-Strauss syndrome, renal-lim- involves vessels large enough to be ob- lo-proteinases and/or cyclooxygenase ited vasculitis and secondary forms of served in gross pathological specimens activity (18). vasculitis (19). or visualized by angiography; small

477 REVIEW Angiogenesis in vasculitides / N. Maruotti et al.

Table II. Names and defi nitions of vascu- other hand, endothelial cells of newly- (43). TNF-α and IL-6 levels are higher litides adopted by the Chapel Hill Consen- formed vessels express adhesion mol- in acute phase (44), sus Conference. ecules and produce colony-stimulating when , a carrier for free he- Giant cell arteritis factors and chemokines for leukocytes moglobin with angiogenic properties, Granulomatosis arteritis of the aorta and its ma- (28-32). In this way, circulating leuko- is highly produced (45). jor branches, with a predilection for the extracra- cytes arrive to sites of infl ammation Constitutive (PECAM-1, ICAM-1, nial branches of the carotid artery. Often involves where constitute a further infl ammatory ICAM-2, and P-selectin) and inducible the temporal artery. stimulus (32, 33). Antineutrophil cyto- (E-selectin and VCAM-1) endothelial Takayasu’s arteritisarteritis plasmic (ANCA) potentiate cell adhesion molecules for leukocytes Granulomatosis arteritis of the aorta and its ma- jor branches. and mediated en- are over-expressed by endothelial cells dothelial cell activation (34). of adventitial microvessels and neo- Polyarteritis nodosa Necrotizing infl ammation of the medium-sized vessels in giant cell arteritis vascular or small arteries. Angiogenesis in giant cell arteritis lesions. Leukocytes interactions with Giant cell arteritis is a vasculitis that these ligands are responsible for the Kawasaki’s diseasedisease Arteritis involving large, medium sized and small mainly affects extracranial medium- formation of infl ammatory infi ltrates arteries. Coronary arteries are often involved. sized and large arteries, aorta and its in giant cell arteritis lesions (32). In + Wegener’s granulomatosisgranulomatosis principal branches (35, 36). The aorta adventitia, CD4 T cells produce in- Necrotizing vasculitis affecting small to medi- typically demonstrates aortic root dila- terferon-γ (IFN-γ). IFN-γ is corre- um-sized vessels. tation, with medial dissection in oc- lated with multinucleated giant cells Churg-Strauss syndrome casional cases of aortic rupture. The (MGCs) formation and intimal hy- Necrotizing vasculitis affecting small to medi- intima is wrinkled demonstrating a perplasia (46). MGCs are specialized um-sized vessels. tree-back appearance. Histologically, fused cells derived by Microscopic polyangitis the infl ammatory infi ltrate consists of that accumulate in media-intima of ar- Necrotizing vasculitis affecting small vessels. lymphocytes, plasma cells and histio- terial wall where are involved in VEGF Henoch-Schönlein purpura cytes. There is disruption of the internal production. VEGF and IFN-γ, in addi- Vasculitis affecting small vessels. elastic lamina with fragmentation and a tion to tissue hypoxia subsequent to Essential cryoglobulinemia vasculitis giant cell reaction. The disruption may arterial wall thickening and luminal Vasculitis affecting small vessels be accompanied by a signifi cant degree stenosis, are probably responsible of Cutaneous leukocytoclastic vasculitis of necrosis. Vessel occlusion occurring the angiogenesis in giant cell arteritis Isolated cutaneous leukocytoclastic angitis with- in giant cell arteritis causes ischemia. lesions (47). Blindness, stroke, and out systemic vasculitis. Cid et al. (9) have hypothesized that jaw claudication are often seen in giant angiogenesis has an essential role in cell arteritis patients with high levels vessel vasculitis involves capillaries, reducing ischemic tissue damage above of IFN-γ in their lesions (46). On the post-capillary venules and arterioles. all in giant cell arteritis target organs contrary, systemic manifestations in Several studies have demonstrated (37), such as small arteries supplying giant cell arteritis patients are well cor- that angiogenesis is involved in the the optic nerve, and potentiates infl am- related with low levels of IFN-γ (47). pathogenesis of vasculitides, such as mation via expression of adhesion Interestingly, a microsatellite dinucle- Wegener’s granulomatosis, Takayasu’s molecules and production of colony- otide (CA) repeat polymorphism in the arteritis, giant cell arteritis, Kawasaki stimulating factors and chemokines for fi rst intron of the IFN-γ gene was asso- disease, Behçet disease, thromboangii- leukocytes (28-32). Angiogenesis has ciated with some differences between tis obliterans and erythema elevatum been associated with severe infl amma- -proven giant cell arteritis, with diutinum. The angiogenic response is tion in giant cell arteritis (32). On the or without visual ischemic manifes- more intense in small vessel vasculitis, other hand, severe infl ammation, mani- tations. In this regard, an association as compared to medium- and large- fested by very high levels of erythro- between a high IFN-γ producer allele vessels vasculitis, because angiogen- cyte sedimentation rate greater than with giant cell arteritis patients who esis generally involves capillary and 100 mm/1st hour or chronic anemia, has experienced visual ischemic events, post-capillary venules. The hypoxic been associated with protection against and an inverse correlation with indi- environment subsequent to stenosis or visual ischemic manifestations or other viduals carrying a low IFN-γ producer occlusion of the vascular lumen is a severe ischemic manifestations of this allele was found (48). Also, a func- potent signal for the generation of new vasculitis (38-40). tional VEGF-634 G→C gene polymor- blood vessels. VEGF, FGF-2, TGF-β, PDGF, TNF-α, phism was found to be associated with A dual role of angiogenesis in vascu- monocyte chemoattractant -1 severe ischemic complications in giant litides has been proposed (9). On the one (MCP-1) and IL-8 have been observed cell arteritis patients from Northwest- hand, angiogenesis may be a compen- in giant cell arteritis lesions (41, 42). ern Spain (49). The low VEGF pro- satory response to ischemia and to the Moreover, high levels of VEGF, FGF-2 ducer VEGF-634 G allele of this ge- increased metabolic activity above all and soluble ICAM-1 have been found netic polymorphism was signifi cantly in strong acute phase of disease. On the in sera of giant cell arteritis patients overexpressed in giant cell arteritis

478 Angiogenesis in vasculitides / N. Maruotti et al. REVIEW patients with ischemic complications (78) have demonstrated that the inti- do not express E-selectin and VCAM- and additionally, a higher risk of de- mal thickening and angiogenesis are 1, such as endothelial cells of newly- veloping severe ischemic complica- coupled in giant cell arteritis and that formed blood vessels in polyarteritis tions was observed for VEGF-634 GG the capillary neovessels within the in- nodosa and giant cell arteritis (29, 32). homozygous individuals (49). fl amed temporal artery wall contain This particular feature may be due to MGCs are also involved in elastic decorin. the vasculitic process on luminal en- membranes degradation via matrix dothelial cells. (MMP)-2 produc- Angiogenesis in Kawasaki disease tion (50-52). Moreover, MGCs pro- Kawasaki disease is a vasculitis of Angiogenesis in Behçet’s disease duce PDGF-AA and PDGF-BB, both young childhood, characterized by an- Behçet’s disease is characterized by in- involved in intimal proliferation (53). eurysmal dilatation and acute thrombo- creased VEGF expression in oral aph- Giant cell arteritis is characterized by sis of coronary arteries (79-83). Kawa- thous lesions and in the ocular infl am- the release, in the systemic acute-phase, saki disease lesions are characterized mation (89, 90) and by increased inter- of proinfl ammatory cytokines, such as by thinning of vascular media, infl am- leukin-8 levels in synovial fl uids (91). IL-1, TNF-α, and IL-6 (54), which mation and destruction of the extra- Moreover, increased levels of VEGF may infl uence vascular responses such cellular matrix in the internal elastic and MCP-1 were detected in sera of as vessel occlusion or regeneration, lamina and in the trilaminar structure Behçet disease patients (92). involved in the pathogenesis of giant of the vascular wall (79, 80, 83, 84). Recombinant human interferon alpha-2a cell arteritis infl ammatory lesions (28, Fibrosis, granulation and angiogenesis is effective in ocular Behçet’s disease, 55, 56). IL-6-induced angiogenesis is have been seen in these lesions (79, leading to signifi cant improvement of responsible of infl ammation in giant 80, 83-85). Increased VEGF levels vision and complete remission of ocu- cell arteritis and patients with elevated have been found in Kawasaki disease lar vasculitis in the majority of patients IL-6 levels needed higher corticoster- and TGF-β1 has been demonstrated to (93). The mode of action of interferon oid dosage to limit their infl ammatory upregulate VEGF expression in acute may be explained by an anti-angiogenic activity (44, 57, 58). phase of disease (86). Moreover, en- effect, as it has been demonstrated since Decorin, a chondroitin/dermatan sul- dothelial cells of newly-formed blood 1980, when interferon alpha was shown fate proteoglycan of the extracellular vessels in myointima and adventitia of to inhibit endothelial cell migration in a matrix (59), has been found in giant Kawasaki disease coronary artery an- dose-dependent manner (94). cell arteritis lesions (60). Even if no eurysms produce high levels of MMP- factors responsible for the induction 2 (84). Moreover, Gavin et al. (84) Angiogenesis in thromboangiitis of decorin production have been still have demonstrated that in Kawasaki obliterans found, it is known that endothelial disease coronary aneurysms, MMP-9 Angiogenesis plays a crucial role in the cells of newly-formed vessels in giant was also expressed, but its expression infl ammatory process of thromboangii- cell arteritis temporal artery may pro- is not confi ned to aneurysmal arteries. tis obliterans. Vascular lesions are char- duce decorin. Decorin probably inter- Systemic arterial expression of MMP-9 acterized by increased levels of TNF-α acts with type I collagen (61, 62) and in acute Kawasaki disease, even in ab- and ICAM-1-, VCAM-1- and E-selectin fi bronectin (63, 64), two extracellular sence of infl ammatory changes in the are expressed on the endothelial cells matrix , and may induce en- vessel, suggests induction by a circu- of thromboangiitis obliterans newly- dothelial cells proliferation by modify- lating factor, or by an infectious agent formed vessels contributing to leuko- ing the structural organization of these with tropism for arterial tissue. Moreo- cyte adhesion (95). molecules (65, 66). It was found that ver, the signifi cantly elevated MMP-9 when cultured endothelial cells spon- levels during acute phase of Kawasaki Angiogenesis in leukocytoclastic taneously change their morphology disease may refl ect vascular remod- vasculitis from a polygonal shape to a sprouting eling or an infl ammatory response to Erythema elevatum diutinum, a vari- phenotype they concomitantly initiate a microbial agent, suggesting a patho- ation of leukocytoclastic vasculitis, is decorin synthesis and depostion, indi- physiological role for MMP-9 in coro- characterized by cutaneous lesions over cating that decorin is associated with nary aneurysm formation (87). the shins, buttocks and extensor sur- angiogenesis (67). Decorin, a ligand Miura et al. (88) have demonstrated faces of the knees, elbows, and fi nger for the epidermal growth factor recep- that endothelial cells of newly-formed joints (96). Macroscopically, erythema tor (EGF-R) (68), that is involved in blood vessels in coronary artery aneu- elevatum diutinum lesions in the acute endothelial cells proliferation, inhibits rysm in Kawasaki disease express E- infl ammatory phase are raised ery- of endothelial cells (69), in- selectin, involved in leukocytes adhe- thematous plaques, resolving in fi brous duces collagenase expression (70) and sion on endothelial cells, and VCAM- nodules with storiform or concentric phospholipase A2 activity (71), both 1, important in leukocytes adhesion fi brosis (97). Microscopically, three involved in angiogenesis (72-74), in- and extravasation into tissues. On the stages are described: a fi rst stage char- hibits TGF-beta (75, 76) and induces contrary, luminal endothelial cells of acterized by capillary proliferation and FGF-2 activity (77). Nelimarka et al. coronary arteries without aneurysms fi brinoid degeneration of vessel wall; a

479 REVIEW Angiogenesis in vasculitides / N. Maruotti et al. second stage characterized by fi brosis, is probably involved in endothelial cell research has been concentrated on the dermal aggregates of and differentiation and proliferation in sys- role of angiogenesis in cancer, and areas of granulation tissue; a third stage temic vasculitis, including Wegener’s inhibition of angiogenesis is a major characterized by fi brosis of the dermis granulomatosis, Takayasu’s arteritis area of therapeutic development for the with small foci of persistent leukocyto- and giant cell arteritis. Cid et al. (45) treatment of this disease. It is conceiv- clastic vasculitis. found a potent angiogenic activity in able that this therapeutical approach Dermal dendrocytes (DD), present in association with high levels of hap- might involve also the treatment of the adventitial and reticular dermis, toglobin in sera from patients affected chronic infl ammatory diseases, such as have phagocytic and antigen present- by Wegener’s granulomatosis, Taka- vasculitides. ing function and may modulate the yasu’s arteritis and giant cell arteritis, regulatory mechanisms of deposition using both in vitro and in vivo angio- References of extracellular macromolecules in the genesis models. Haptoglobin levels are 1. RISAU W: Mechanisms of angiogenesis. dermis. Moreover, DD are involved in particularly high in Wegener’s granulo- Nature 1997; 386: 671-4. the tissue repair mechanisms, fi brogen- matosis patients in the period of clini- 2. PEPPER MS: Manipulating angiogenesis: from basic science to the bedside. Arter esis and angiogenesis (98, 99). Pacheco cally active disease characterized by Thromb Vasc Biol 1997; 17: 605-19. et al. (100) have demonstrated that DD intense angiogenic activity. 3. DAMERON KM, VOLPERT OV, TAINSKY MA, may play a role in infl ammatory skin BOUCK N: Control of angiogenesis in fi brob- lasts by p53 regulation of thrombospondin- diseases and found that DD in erythema Concluding remarks 1. Science 1994; 265: 1582-4. elevatum diutinum and leukocytoclas- In vasculitides, angiogenesis may be 4. O’REILLY MS, HOLMGREN L, SHING Y et al.: tic vasculitis are increased in number, a compensatory response to ischemia Angiostatin: a novel hypertrophic and show stellate mor- and to the increased metabolic activity that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 11994;994; 79: phology. Even if erythema elevatum and may be also a further infl ammatory 315-28. diutinum was characterized by a higher stimulus because endothelial cells of 5. O’REILLY MS, BOEHM T, SHING Y et al.: number of newly-formed blood ves- newly-formed vessels express adhesion Endostatin: an endogenous inhibitor of ang- sels than leukocytoclastic vasculitis, molecules and produce colony-stimu- iogenesis and tumor growth. Cell 1997;1997; 88: 277-85. no statistically signifi cant difference in lating factors and chemokines for leu- 6. FIOCCHI C: Infl ammatory bowel disease eti- the number of DD has been observed kocytes (28-33). Even if further studies ology and pathogenesis. Gastroenterology between these two pathological condi- are needed to elucidate the pathogenic 1998; 115: 182-205. tions (100). mechanism of vasculitides, the emer- 7. BOUSVAROS A, LEICHTNER A, ZURA- KOWSKI D et al.: Elevated serum vascular gency of angiogenesis as a key player endothelial growth factor in children and Angiogenesis in lymphocytic in the pathogenic events leading to We- young adults with Crohn’s disease. Dig Dis vasculitis gener’s granulomatosis, Takayasu’s ar- Sci 1999; 44: 424-30. Lymphocytic vasculitis can be second- teritis, giant cell arteritis, Kawasaki dis- 8. LEE SS, JOO YS, KIM WU et al.: Vascular en- dothelial growth factor levels in the serum ary to treatment of rheumatoid arthritis ease, Behçet’s disease, thromboangiitis and synovial fl uid of patients with rheuma- and Crohn’s disease with infl iximab, obliterans and erythema elevatum diuti- toid arthritis. Clin Exp Rheumatol 2001;2001; 19:19: etanercept, or adalimumab (26, 27). num vasculitides, may provide a basis 321-4. 9. CID MC, HERNÁNDEZ-RODRÍGUEZ J, ESTE- These drugs rarely cause autoimmune for a rational approach to the develop- BAN MJ et al.: Tissue and Serum angiogenic disorders, such as vasculitis and lupus, ment of an anti-angiogenic therapy. activity is associated with low prevalence probably due to low TNF-α levels (101- It is well established that the angiogen- of ischemic complications in patients with 106), which are unable to suppress au- ic phenotype results from the imbal- giant-cell arteritis. Circulation 2002; 106: 1664. toreactive B and T cells responsible in ance between positive and negative 10. MEDINA J, SANZ-CAMENO P, GARCÍA-BUEY turn of autoimmune reactions (107). regulator factors, so that the contribu- L, MARTÍN-VÍLCHEZ S, LÓPEZ-CABRERA M, Srivastava et al. (27) found an increase tion of each angiogenic factor may play MORENO-OTERO R: Evidence of angiogen- of VEGF and chemokine levels, espe- a different role in the defi nition of the esis in primary biliary cirrhosis: an immuno- histochemical descriptive study. J Hepatol cially RANTES, in serum of a patient angiogenic phenotype in vasculitides, 2005; 42: 124-31. with T-cell lymphocytic vasculitis sec- when increased production of ang- 11. BALLARA SC, MIOTLA JM, PALEOLOG EM: ondary to treatment with etanercept, iogenic stimuli and/or reduced produc- New vessels, new approaches: angiogenesis which worsened signifi cantly with tion of angiogenic inhibitors may lead as a therapeutic target in musculoskeletal disorders. Int J Exp Pathol 11999;999; 80: 235- switch to infl iximab. Moreover, ang- to abnormal neovascularization. 50. iogenic mediators, including TNF-α, The development of a clinical trial 12. BIAN XW, CHEN JH, JIANG XF, BAI JS, WANG IL-1β, IL-15, IL-18, were found in the requires the identifi cation and charac- QL, ZHANG X: Angiogenesis as an immu- vasculitic lesions of the patient. terization of the physiological targets nopharmacologic target in infl ammation and cancer. Int Immunopharmacol 2004;2004; 4: involved in angio-stimulatory and an- 1537-47. Further evidences of angiogenesis in gio-inhibitory activities. 13. CLAUSS M, GERLACH M, GERLACH H et vasculitides: haptoglobin Angiogenesis inhibitors are now being al.: Vascular permeability factor: a tumor- derived polypeptide that induces endothe- Haptoglobin, a carrier for free hemo- approved and introduced into medical lial cell and monocyte procoagulant ac- globin, has angiogenic properties and practice throughout the world. Much tivity, and promotes monocyte migration.

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J Exp Med 1990;1990; 172: 1535-45. Angiogenesis in rheumatoid arthritis: patho- associated with higher corticosteroid re- 14. MELDER RJ, KOENIG GC, WITWER BP, SA- genic and clinical signifi cance. J Invest Med quirements and longer duration of therapy FABAKHSH N, MUNN LL, JAIN RK: During 1998; 46: 27-41. in patients with giant-cell arteritis. Arthritis angiogenesis, vascular endothelial growth 31. CARMELIET P, JAIN RK: Angiogenesis in Rheum 2002; 47: 29-35. factor and basic fi broblast growth factor cancer and other diseases. Nature 2000; 407: 45. CID MC, GRANT DS, HOFFMAN GS, AUER- regulate natural killer cell adhesion to tumor 249-57. BACH R, FAUCI AS, KLEINMAN HK: Iden- endothelium. Nat Med 1996;1996; 2: 992-7. 32. CID MC, CEBRIÁN M, FONT C et al.: Cell tifi cation of haptoglobin as an angiogenic 15. FOLKMAN J, KLAGSBRUN M, SASSE J, adhesion molecules in the development of factor in sera from patients with systemic WADZINSKI M, INGBER D, VLODAVSKY I: infl ammatory infi ltrates in giant cell arteri- vasculitis. J Clin Invest 11993;993; 991:1: 9977-85.77-85. A -binding angiogenic protein – ba- tis: infl ammation-induced angiogenesis as 46. WEYAND CM, TETZLAFF N, BJORNSSON J, sic fi broblast growth factor – is stored within the preferential site of leukocyte/endothelial BRACK A, YOUNGE B, GORONZY JJ: Disease basement membrane. Am J Pathol 1988; cell interactions. Arthritis Rheum 2000; 43: patterns and tissue profi les in giant 130: 393-400. 184-94. cell arteritis. Arthritis Rheum 1997; 40: 19- 16. BUCKLEY CD, AMFT N, BRADFIELD PF et 33. CID MC, ESPARZA J, JUAN M et al.: Sign- 26. al.: Persistent induction of the chemokine aling through CD50 (ICAM-3) stimulates 47. KAISER M, YOUNGE B, BJÖRNSSON J, receptor CXCR4 by TGF-beta 1 on synovial T lymphocyte binding to human umbilical GORONZY JJ, WEYAND CM: Formation of T cells contributes to their accumulation vein endothelial cells and extracellular ma- new vasa vasorum in vasculitis. Am J Pathol within the rheumatoid synovium. J Immunol trix proteins via an increase in beta 1 and 1999; 155: 765-74. 2000; 165: 3423-9. beta 2 function. Eur J Immunol 48. GONZALES-GAY MA, HAJEER AH, DABAB- 17. BUCKLEY CD, PILLING D, LORD JM, AKBAR 1994; 24: 1377-82. NEH A et al.: Interferon-gamma gene micro- AN, SCHEEL-TOELLNER D, SALMON M: Fi- 34. CID MC, SEGARRA M, GARCIA-MARTINEZ satellite polymorphisms in patients with bi- broblasts regulate the switch from acute re- A, HERNANDEZ-RODRIGUEZ J: Endothelial opsy-proven giant cell arteritis and isolated solving to chronic persistent infl ammation. cells, antineutrophil cytoplasmic antibodies, . Clin Exp Rheuma- Trends Immunol 22001;001; 22: 199-204. and cytokines in the pathogenesis of sys- tol 22004;004; 2222 ((Suppl.Suppl. 336):6): SS18-20.18-20. 18. MARUOTTI N, CANTATORE FP, CRIVEL- temic vasculitis. Curr Rheumatol Rep 2004; 49. RUEDA B, LOPEZ-NEVOT MA, LOPEZ- LATO E, VACCA A, RIBATTI D: Macrophages 6: 184-94. DIAZ MJ, GARCIA-PORRUA C, MARTIN J, in rheumatoid arthritis. Histol Histopathol 35. NORDBORG E, NORDBORG C, MALMVALL GONZALES-GAY MA: A functional variant 2007; 22: 581-6. BE, ANDERSSON R, BENGTSSON BA: Gi- of vascular endothelial growth factor is as- 19. SALEH A, STONE JH: Classifi cation and di- ant cell arteritis. Rheum Dis Clin North Am sociated with severe ischemic complications agnostic criteria in systemic vasculitis. Best 1995; 21: 1013-26. in giant cell arteritis. J Rheumatol 2005;2005; 332:2: Pract Res Clin Rheumatol 2005; 19: 209- 36. HUNDER GG: Giant cell arteritis and poly- 1737-41. 21. myalgia rheumatica. Med Clin North Am 50. LIE JT: Histopathologic specifi city of sys- 20. COPEMAN PWM, RYAN TJ: The problems of 1997; 81: 195-219. temic vasculitis. Rheum Dis Clin North Am classifi cation of cutaneous angiitis with ref- 37. ESTEBAN MJ, FONT C, HERNÁNDEZ-RO- 1995; 21: 883-909. erence to histopathology and pathogenesis. DRÍGUEZ J et al.: Small-vessel vasculitis 51. WEYAND CM, WAGNER AD, BJORNSSON J, Br J Dermatol 11970;970; 882:2: 22-14.-14. surrounding a spared temporal artery: clini- GORONZY JJ: Correlation of the topographi- 21. CEM AR M, SOYSAL T, HATEMI G, SALI- cal and pathologic fi ndings in a series of cal arrangement and the functional pattern HOGLU A, YAZICI H, ULKU B: Successful twenty-eight patients. Arthritis Rheum 2001; of tissue-infi ltrating macrophages in giant management of cryoglobulinemia-induced 44: 1387-95. cell arteritis. J Clin Invest 1996;1996; 998:8: 11642-642- leukocytoclastic vasculitis with 38. SALVARANI C, CIMINO L, MACCHIONI P et 9. in a patient with multiple myeloma. Ann He- al: Risk factors for visual loss in an Italian 52. NIKKARI ST, HOYHTYA M, ISOLA J, NIKKARI matol 22005;005; 884:4: 6609-13.09-13. population-based cohort of patients with gi- T: Macrophages contain 92-kd gelatinase 22. KOSSARD S: Defi ning lymphocytic vasculi- ant cell arteritis. Arthritis Rheum 2005; 53: (MMP-9) at the site of degenerated internal tis. Australas J Dermatol 22000;000; 441:1: 1149-55.49-55. 293-7. elastic lamina in temporal arteritis. Am J 23. HAMMAR SP: Granulomatous vasculitis. 39. GONZALES-GAY MA, GARCIA-PORRUA C, Pathol 11996;996; 1149:49: 11427-33.427-33. Semin Respir Infect 11995;995; 110:0: 1107-20.07-20. LLORCA J et al.: Visual manifestations of 53. KAISER M, WEYAND CM, BJORNSSON J, 24. LUQMANI RA, ROBINSON H: Introduction giant cell arteritis. Trends and clinical spec- GORONZY JJ: Platelet-derived growth factor, to, and classifi cation of the systemic vascu- trum in 161 patients. Medicine (Baltimore) intimal hyperplasia, and ischemic complica- litides. Best Pract Res Clin Rheumatol 22001001; 2000; 79: 283-92. tions in giant cell arteritis. Arthritis Rheum 15: 187-202. 40. GONZALES-GAY MA, BARROS S, LOPEZ- 1998; 41: 623-33. 25. NIKKARI S, RELMAN A: Molecular ap- DIAZ MJ, GARCIA-PORRUA C, SANCHEZ- 54. BAUMANN H, GAULDIE J: The acute phase proaches for identifi cation of infectious ANDRADE A, LLORCA J: Giant cell arteritis: response. Immunol Today 1994; 15: 74-80. agents in Wegener’s granulomatosis. Curr disease patterns of clinical presentation in a 55. ROSSI V, BREVIARIO F, GHEZZI P, DEJANA Opin Rheumatol 11999;999; 111:1: 11-6.11-6. series of 240 patients. Medicine (Baltimore) E, MANTOVANI A: Prostacyclin synthesis in- 26. SRIVASTAVA MD: Immunomodulatory ef- 2005; 84: 269-76. duced by in vascular cells by interleukin-1. fects of etanercept (TNFR:Fc) and its use in 41. WEYAND CM, HICOK KC, HUNDER GG, Science 1985; 225: 174-6. a patient with Crohn’s disease. Res Commun GORONZY JJ: Tissue cytokine patterns in 56. MANTOVANI A, GARLANDA C, INTRONA Mol Pathol Pharmacol 22001;001; 1109:09: 1125-41.25-41. patients with polymyalgia rheumatica and M, VECCHI A: Regulation of endothelial 27. SRIVASTAVA MD, ALEXANDER F, TUTHILL giant-cell arteritis. Ann Intern Med 1994;1994; cell function by pro- and anti-infl ammatory RJ: of cutaneous vasculitis 121: 484-91. cytokines. Transplant Proc 1998; 30: 4239- associated with both etanercept and infl ixi- 42. WEYAND CM, GORONZY JJ: Arterial wall 43. mab. Scand J Immunol 2005; 61: 329-36. injury in giant-cell arteritis. Arthritis Rheum 57. HERNÁNDEZ-RODRÍGUEZ J, SEGARRA M, 28. MANTOVANI A, BUSSOLINO F, DEJANA E: 1999; 42: 844-53. VILARDELL C et al.: Elevated production of Cytokine regulation of endothelial cell func- 43. COLL-VINENT B, VILARDELL C, FONT C et interleukin-6 is associated with a lower inci- tion. FASEB J 1992;1992; 66:: 22591-9.591-9. al.: Circulating soluble adhesion molecules dence of disease-related ischemic events in 29. COLL-VINENT B, CEBRIAN M, CID MC et in patients with giant-cell arteritis: correla- patients with giant-cell arteritis. Circulation al.: Dynamic pattern of endothelial cell ad- tion between soluble intercellular adhesion 2003; 107: 2428-34. hesion molecule expression in muscle and molecule-1 (SCAM-1) and disease activity. 58. HERNÁNDEZ-RODRÍGUEZ J, SEGARRA M, perineural vessels from patients with classic Ann Rheum Dis 1999; 58: 189-92. VILARDELL C et al.: Tissue production of polyarteritis nodosa. Arthritis Rheum 1998; 44. HERNÁNDEZ-RODRÍGUEZ J, GARCÍA-MAR- proinfl ammatory cytokines (IL-1ß, TNF- 41: 435-44. TÍNEZ A, CASADEMONT J et al.: A strong α, and IL-6) correlates with the intensity 30. SZEKANECZ A, SZEGEDI G, KOCH AE: initial systemic infl ammatory response is of the systemic infl ammatory response and

481 REVIEW Angiogenesis in vasculitides / N. Maruotti et al.

with corticosteroid requirements in giant- genesis. Biochim Biophys Acta 1998; 1392: acute Kawasaki disease. Pediatr Infect Dis cell arteritis. Rheumatology 2004; 43: 294- 145-52. J 2004; 23: 931-6. 301. 73. MACH F, SCHONBECK U, FABUNMI RP et 89. NAM EJ, HAN SW, KIM SU et al.: Association 59. IOZZO RV: The family of the small leucine- al.: T lymphocytes induce endothelial cell of vascular endothelial growth factor gene rich proteoglycans: key regulators of matrix matrix metalloproteinase expression by a polymorphisms with Behçet disease in a assembly and cellular growth. Crit Rev Bio- CD40L-dependent mechanism: implications Korean population. Hum Immunol 2005;2005; 66:66: chem Mol Biol 11997;997; 332:2: 1141-74.41-74. for tubule formation. Am J Pathol 1999; 1068-73. 60. NELIMARKKA L, SALMINEN H, KUOPIO T 154: 229-38. 90. YACIN B, ARDA N, TEZEL GG, ERMAN M, et al.: Decorin is produced by capillary en- 74. O’CONNOR DS, SCHECHNER JS, ADIDA C et ALLI N: 1Expressions of vascular endothe- dothelial cells in infl ammation-associated al.: Control of apoptosis during angiogen- lial growth factor and CD34 in oral aphthous angiogenesis. Am J Pathol 2001;2001; 158:158: 345-345- esis by survivin expression in endothelial lesions of Behçet’s disease. Anal Quant Cy- 53. cells. Am J Pathol 2000;2000; 1156:56: 3393-8.93-8. tol Histol 2006; 28: 303-6. 61. SCHÖNHERR E, WITSCH-PREHM P, HAR- 75. YAMAGUCHI Y, MANN DM, RUOSLAHTI E: 91. ERDEM H, PAY S, SERDAR M et al.: Different RACH B, ROBENEK H, RAUTERBERG J, Negative regulation of transforming growth ELR (+) angiogenic CXC chemokine pro- KRESSE H: Interaction of biglycan with type factor-beta by the proteoglycan decorin. Na- fi les in synovial fl uid of patients with BD, I collagen. J Biol Chem 1995; 270: 2776- ture 1990; 346: 281-4. familial Mediterranean , rheumatoid 83. 76. HILDEBRAND A, ROMARIS M, RASMUSSEN arthritis, and osteoarthritis. Rheumatol Int 62. SVENSSON L, HEINEGARD D, OLDBERG A: LM et al.: Interaction of the small interstitial 2005; 26: 162-7. Decorin-binding sites for collagen type I are proteoglycans biglycan, decorin and fi bro- 92. BOZOGLU E, DINC A, ERDEM H, PAY S, mainly located in leucine-rich repeats 4-5. modulin with transforming growth factor SIMSEK I, KOCAR IH: Vascular endothelial J Biol Chem 1995; 270: 20712-6. beta. Biochem J 11994;994; 3302:02: 5527-34.27-34. growth factor and monocyte chemoattract- 63. LEWANDOWSKA K, CHOI HU, ROSENBERG 77. PENC SF, POMAHAC B, WINKLER T et al.: ant protein-1 in BD patients with venous LC, ZARDI L, CULP LA: -medi- Dermatan sulfate released after injury is a thrombosis. Clin Exp Rheumatol 2005;2005; 23:23: ated adhesion of fi broblasts: inhibition by potent promoter of fi broblast growth factor- S42-8. dermatan sulfate proteoglycan and evidence 2 function. J Biol Chem 1998; 273: 28116- 93. KÖTTER I, ZIERHUT M, ECKSTEIN AK et al.: for a cryptic glycosaminoglycan-binding 21. Human recombinant interferon alfa-2a for domain. J Cell Biol 11987;987; 1105:05: 11443-54.443-54. 78. NELIMARKKA L, SALMINEN H, KUOPIO T the treatment of Behçet’s disease with sight 64. SCHMIDT G, ROBENEK H, HARRACH B et et al.: Decorin is produced by capillary en- threatening posterior or panuveitis. Br J al.: Interaction of small dermatan sulfate dothelial cells in infl ammation-associated Ophthalmol 2003;2003; 887:7: 4423-31.23-31. proteoglycan from fi broblasts with fi bronec- angiogenesis. Am J Pathol 2001;2001; 158:158: 345-345- 94. BROUTY-BOYE D, ZETTER BR: Inhibition tin. J Cell Biol 11987;987; 1104:04: 11683-91.683-91. 53. of cell motility by interferon. Science 1980; 65. JACKSON CJ, JENKINS KL: Type I collagen 79. FUJIWARA H, HAMASHIMA Y: Pathology of 208: 516-8. fi brils promote rapid vascular tube forma- the heart in Kawasaki disease. Pediatrics 95. HALACHEVA K, GULUBOVA MV, MANOLO- tion upon contact with the apical side of cul- 1978; 61: 100-7. VA I, PETKOV D: Expression of ICAM-1, tured endothelium. Exp Cell Res 1991; 192: 80. AMANO S, HAZAMA F, HAMASHIMA Y: Pa- VCAM-1, E-selectin and TNF-alpha on the 319-23. thology of Kawasaki disease: pathology and endothelium of femoral and iliac arteries in 66. VERNON RB, LARA SL, DRAKE CJ et al.: Or- morphogenesis of the vascular changes. Jpn thromboangiitis obliterans. Acta Histochem ganized type I collagen infl uences endothe- Circ J 11979;979; 443:3: 6633-43.33-43. 2002; 104: 177-84. lial patterns during “spontaneous angiogen- 81. KATO H, INOUE O, AKAGI T: Kawasaki dis- 96. KATZ SI: Infl ammatory and neoplastic dis- esis in vitro”: planar cultures as models of ease: cardiac problems and management. orders of the dermis: Erythema elevatum di- vascular development. In Vitro Cell Dev Pediatr Rev 1988; 9: 209-17. utinum. In FREEDBERG IM, EISEN AZ, WOLF Biol Anim 1995; 31: 120-31. 82. ROWLEY AH, SHULMAN ST: Kawasaki syn- K et al. (Eds.): Fitzpatrick’s DDermatologyermatology iinn 67. JARVELAIMEN HT, IRUELA-ARISPE ML, drome. Pediatr Clin North Am 1999; 46: General Medicine, 5th ed. New York, Mc- KINSELLA MG, SANDELL LJ, SAGE EH, 313-29. Graw-Hill 1993: 1: 1124. WIGHT TN: Expression of decorin by sprout- 83. NAOE S, TAKAHASHI K, MASUDA H, TANA- 97. LE BOIT PE, BENEDICT YEN TSB, WINTROUB ing bovine aortic endothelial cells exhibiting KA N: Kawasaki disease with particular em- B: The evolution of lesion in erythema ele- angiogenesis in vitro. Exp Cell Res 1992, phasis on arterial lesions. Acta Pathol Jpn vatum diutinum. Am J Dermatopathol 1986;1986; 203: 395-401. 1991; 41: 785-97. 8: 392. 68. IOZZO RV, MOSCATELLO DK, MCQUILLAN 84. GAVIN PJ, CRAWFORD SE, SHULMAN ST, 98. NICKOLOFF BJ, GRIFFTHS CEM: The spin- DJ, EICHSTETTER I: Decorin is a biological GARCIA FL, ROWLEY AH: Systemic arterial dle-shaped cells in cutaneous Kaposi’s sar- ligand for the epidermal growth factor re- expression of matrix metalloproteinases 2 coma. Histologic simulators include factor ceptor. J Biol Chem 1999; 274: 4489-92. and 9 in acute Kawasaki disease. Arterio- XIIIa dermal dendrocytes. Am J Pathol 69. SCHÖNHERR E, O’CONNELL BC, SCHITTNY scler Thromb Vasc Biol 2003; 23: 576-81. 1989; 135: 793-800. J et al.: Paracrine or virus-mediated induc- 85. MITCHELL RN, COTRAN RS: Repair: cell re- 99. PENNEYS SP: Factor XIII expression in the tion of decorin expression by endothelial generation, fi brosis, and wound healing. In skin: observations and a hypothesis. J Am cells contributes to tube formation and pre- KUMAR V, COTRAN RS, ROBBINS SL (Eds.) Acad Dermatol 1990; 22: 484-8. vention of apoptosis in collagen lattices. Eur Basic Pathology. 6th ed. Philadelphia: WB 100. PACHECO LS, SOTTO MN: Factor XIIIa+ J Cell Biol 11999;999; 778:8: 444-55.4-55. Saunders, 1997: 47-59. dermal dendrocytes in erythema elevatum 70. HUTTENLOCHER A, WERB Z, TREMBLE P, 86. TERAI M, YASUKAWA K, NARUMOTO S, diutinum and ordinary cutaneous leukocyto- HUHTALA P, ROSENBERG L, DAMSKY CH: TATENO S, OANA S, KOHNO Y: Vascular en- clastic vasculitis lesions. J Cutan Pathol Decorin regulates collagenase gene expres- dothelial growth factor in acute Kawasaki 2000; 27: 136-40. sion in fi broblasts adhering to vitronectin. disease. Am J Cardiol 1999; 83: 337-9. 101. GALARIA NA, WERTH VP, SCHUMACHER Matrix Biol 11996;996; 115:5: 2239-50.39-50. 87. CHUA PK, MELISH ME, YU Q, YANAGIHARA HR: Leukocytoclastic vasculitis due to 71. SARTIPY P, JOHANSEN B, GASVIK K, HURT R, YAMAMOTO KS, NERURKAR VR: El- etanercept. J Rheumatol 2000; 27: 2041-4. CAMEJO E: Molecular basis for the associa- evated levels of matrix metalloproteinase-9 102. MCCAIN ME, QUINET RJ, DAVIS WE: Etan- tion of group IIA phospholipase A(2) and and tissue inhibitor of metalloproteinase-1 ercept and infl iximab associated with cuta- decorin in human atherosclerotic lesions. during the acute phase of Kawasaki disease. neous vasculitis. Rheumatology 2002; 41: Circ Res 2000; 86: 707-14. Clin Diagn Lab Immunol 2 2003;003; 1 10:0: 3 308-08- 116-7. 72. JACKSON JR, BOLOGNESE B, MANGAR CA, 314. 103. LIVERMORE PA, MURRAY KJ: Anti-tumor HUBBARD WC, MARSHALL LA, WINKLER 88. MIURA M, GARCIA FL, CRAWFORD SE, necrosis factor therapy associated with cu- JD: The role of platelet activating factor and ROWLEY AH: Cell adhesion molecule ex- taneous vasculitis. Rheumatology 2002; 41: other lipid mediators in infl ammatory angio- pression in coronary artery aneurysms in 1450-2.

482 Angiogenesis in vasculitides / N. Maruotti et al. REVIEW

104. SHAKOOR N, MICHALSKA M, HARRIS C, therapy-induced vasculitis: case series. J 2003; 36: 411-3. BLOCK J: Drug-induced systemic lupus ery- Rheumatol 2003;2003; 330:0: 22287-91.287-91. 107. SEO SJ, FIELDS ML, BUCKLER JL et al.: thematosus associated with etanercept thera- 106. MCILWAIN L, CARTER JD, BIN-SAGHEERS, The impact of T helper and T regulatory py. Lancet 2003; 359: 579-80. VASEY FB, NORD J: vas- cells on the regulation of anti-double strand- 105. JARRETT SJ, CUNNANE G, CONAGHAN culitis with leukocytoclastic vasculitis sec- ed DNA B cells. Immunity 2002; 16: 535- PG et al.: Antitumor necrosis factor-alpha ondary to infl iximab. J Clin Gastroenterol 46.

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