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Erschienen in: Arthritis Research & Therapy 2/2007

01.08.2007 | Review

Vasculopathy and disordered angiogenesis in selected rheumatic diseases: rheumatoid arthritis and systemic sclerosis

verfasst von: Alisa E Koch, Oliver Distler

Erschienen in: Arthritis Research & Therapy | Sonderheft 2/2007

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Abstract

Angiogenesis is important in the pathogenesis of systemic inflammatory rheumatic diseases, a family of related disorders that includes rheumatoid arthritis and systemic sclerosis. Rheumatoid arthritis is the rheumatic disease in which the role of angiogenesis has been studied most extensively. However, whereas rheumatoid arthritis is characterized by excessive angiogenesis, the situation is not as clear cut in other rheumatic diseases. For example, systemic sclerosis is characterized by reduced capillary density with insufficient angiogenic responses. Results with angiogenesis inhibitors are controversial, and there is – in parallel – a wide range of upregulated angiogenic factors such as vascular endothelial growth factor. Dysregulation of angiogenesis in systemic sclerosis is accompanied by other pathogenic processes, including fibrosis, autoimmunity and vasculopathy. Animal models with at least partial features of the vasculopathy observed in systemic sclerosis include wound healing models, graft versus host disease models and, in particular, the University of California at Davis line 200 chicken model of systemic sclerosis.
Literatur
1.
Zurück zum Zitat Lowe PM, Lee ML, Jackson CJ, To SS, Cooper AJ, Schrieber L: The endothelium in psoriasis. Br J Dermatol. 1995, 132: 497-505.CrossRefPubMed Lowe PM, Lee ML, Jackson CJ, To SS, Cooper AJ, Schrieber L: The endothelium in psoriasis. Br J Dermatol. 1995, 132: 497-505.CrossRefPubMed
2.
Zurück zum Zitat Koch AE: The role of angiogenesis in rheumatoid arthritis: recent developments. Ann Rheum Dis. 2000, 65-71. 10.1136/ard.59.suppl_1.i65. Suppl 1 Koch AE: The role of angiogenesis in rheumatoid arthritis: recent developments. Ann Rheum Dis. 2000, 65-71. 10.1136/ard.59.suppl_1.i65. Suppl 1
3.
Zurück zum Zitat Koch AE, Harlow LA, Haines GK, Amento EP, Unemori EN, Wong WL, Pope RM, Ferrara N: Vascular endothelial growth factor. A cytokine modulating endothelial function in rheumatoid arthritis. J Immunol. 1994, 152: 4149-4156.PubMed Koch AE, Harlow LA, Haines GK, Amento EP, Unemori EN, Wong WL, Pope RM, Ferrara N: Vascular endothelial growth factor. A cytokine modulating endothelial function in rheumatoid arthritis. J Immunol. 1994, 152: 4149-4156.PubMed
4.
Zurück zum Zitat Cho ML, Cho CS, Min SY, Kim SH, Lee SS, Kim WU, Min DJ, Min JK, Youn J, Hwang SY, Park SH, Kim HY: Cyclosporine inhibition of vascular endothelial growth factor production in rheumatoid synovial fibroblasts. Arthritis Rheum. 2002, 46: 1202-1209. 10.1002/art.10215.CrossRefPubMed Cho ML, Cho CS, Min SY, Kim SH, Lee SS, Kim WU, Min DJ, Min JK, Youn J, Hwang SY, Park SH, Kim HY: Cyclosporine inhibition of vascular endothelial growth factor production in rheumatoid synovial fibroblasts. Arthritis Rheum. 2002, 46: 1202-1209. 10.1002/art.10215.CrossRefPubMed
5.
Zurück zum Zitat Byrne AM, Bouchier-Hayes DJ, Harmey JH: Angiogenic and cell survival functions of vascular endothelial growth factor (VEGF). J Cell Mol Med. 2005, 9: 777-794. 10.1111/j.1582-4934.2005.tb00379.x.CrossRefPubMed Byrne AM, Bouchier-Hayes DJ, Harmey JH: Angiogenic and cell survival functions of vascular endothelial growth factor (VEGF). J Cell Mol Med. 2005, 9: 777-794. 10.1111/j.1582-4934.2005.tb00379.x.CrossRefPubMed
6.
Zurück zum Zitat Sekimoto T, Hamada K, Oike Y, Matsuoka T, Matsumoto M, Chosa E, Suda T, Tajima N, Yamamura K: Effect of direct angiogenesis inhibition in rheumatoid arthritis using a soluble vascular endothelial growth factor receptor 1 chimeric protein. J Rheumatol. 2002, 29: 240-245.PubMed Sekimoto T, Hamada K, Oike Y, Matsuoka T, Matsumoto M, Chosa E, Suda T, Tajima N, Yamamura K: Effect of direct angiogenesis inhibition in rheumatoid arthritis using a soluble vascular endothelial growth factor receptor 1 chimeric protein. J Rheumatol. 2002, 29: 240-245.PubMed
7.
Zurück zum Zitat Lu J, Kasama T, Kobayashi K, Yoda Y, Shiozawa F, Hanyuda M, Negishi M, Ide H, Adachi M: Vascular endothelial growth factor expression and regulation of murine collagen-induced arthritis. J Immunol. 2000, 164: 5922-5927.CrossRefPubMed Lu J, Kasama T, Kobayashi K, Yoda Y, Shiozawa F, Hanyuda M, Negishi M, Ide H, Adachi M: Vascular endothelial growth factor expression and regulation of murine collagen-induced arthritis. J Immunol. 2000, 164: 5922-5927.CrossRefPubMed
8.
Zurück zum Zitat Sone H, Kawakami Y, Sakauchi M, Nakamura Y, Takahashi A, Shimano H, Okuda Y, Segawa T, Suzuki H, Yamada N: Neutralization of vascular endothelial growth factor prevents collagen-induced arthritis and ameliorates established disease in mice. Biochem Biophys Res Commun. 2001, 281: 562-568. 10.1006/bbrc.2001.4395.CrossRefPubMed Sone H, Kawakami Y, Sakauchi M, Nakamura Y, Takahashi A, Shimano H, Okuda Y, Segawa T, Suzuki H, Yamada N: Neutralization of vascular endothelial growth factor prevents collagen-induced arthritis and ameliorates established disease in mice. Biochem Biophys Res Commun. 2001, 281: 562-568. 10.1006/bbrc.2001.4395.CrossRefPubMed
9.
Zurück zum Zitat Miotla J, Maciewicz R, Kendrew J, Feldmann M, Paleolog E: Treatment with soluble VEGF receptor reduces disease severity in murine collagen-induced arthritis. Lab Invest. 2000, 80: 1195-1205.CrossRefPubMed Miotla J, Maciewicz R, Kendrew J, Feldmann M, Paleolog E: Treatment with soluble VEGF receptor reduces disease severity in murine collagen-induced arthritis. Lab Invest. 2000, 80: 1195-1205.CrossRefPubMed
10.
Zurück zum Zitat Luttun A, Tjwa M, Moons L, Wu Y, Angelillo-Scherrer A, Liao F, Nagy JA, Hooper A, Priller J, De Klerck B, et al: Revascularization of ischemic tissues by PlGF treatment, and inhibition of tumor angiogenesis, arthritis and atherosclerosis by anti-Flt1. Nat Med. 2002, 8: 831-840.PubMed Luttun A, Tjwa M, Moons L, Wu Y, Angelillo-Scherrer A, Liao F, Nagy JA, Hooper A, Priller J, De Klerck B, et al: Revascularization of ischemic tissues by PlGF treatment, and inhibition of tumor angiogenesis, arthritis and atherosclerosis by anti-Flt1. Nat Med. 2002, 8: 831-840.PubMed
11.
Zurück zum Zitat Afuwape AO, Feldmann M, Paleolog EM: Adenoviral delivery of soluble VEGF receptor 1 (sFlt-1) abrogates disease activity in murine collagen-induced arthritis. Gene Ther. 2003, 10: 1950-1960. 10.1038/sj.gt.3302104.CrossRefPubMed Afuwape AO, Feldmann M, Paleolog EM: Adenoviral delivery of soluble VEGF receptor 1 (sFlt-1) abrogates disease activity in murine collagen-induced arthritis. Gene Ther. 2003, 10: 1950-1960. 10.1038/sj.gt.3302104.CrossRefPubMed
12.
Zurück zum Zitat Paleolog EM, Young S, Stark AC, McCloskey RV, Feldmann M, Maini RN: Modulation of angiogenic vascular endothelial growth factor by tumor necrosis factor alpha and interleukin-1 in rheumatoid arthritis. Arthritis Rheum. 1998, 41: 258-1265. 10.1002/1529-0131(199807)41:7<1258::AID-ART17>3.0.CO;2-1. Paleolog EM, Young S, Stark AC, McCloskey RV, Feldmann M, Maini RN: Modulation of angiogenic vascular endothelial growth factor by tumor necrosis factor alpha and interleukin-1 in rheumatoid arthritis. Arthritis Rheum. 1998, 41: 258-1265. 10.1002/1529-0131(199807)41:7<1258::AID-ART17>3.0.CO;2-1.
13.
Zurück zum Zitat Koch AE, Polverini PJ, Kunkel SL, Harlow LA, DiPietro LA, Elner VM, Elner SG, Strieter RM: Interleukin-8 as a macrophage-derived mediator of angiogenesis. Science. 1992, 258: 798-1801. 10.1126/science.1281554.CrossRef Koch AE, Polverini PJ, Kunkel SL, Harlow LA, DiPietro LA, Elner VM, Elner SG, Strieter RM: Interleukin-8 as a macrophage-derived mediator of angiogenesis. Science. 1992, 258: 798-1801. 10.1126/science.1281554.CrossRef
14.
Zurück zum Zitat Strieter RM, Burdick MD, Gomperts BN, Belperio JA, Keane MP: CXC chemokines in angiogenesis. Cytokine Growth Factor Rev. 2005, 16: 593-609. 10.1016/j.cytogfr.2005.04.007.CrossRefPubMed Strieter RM, Burdick MD, Gomperts BN, Belperio JA, Keane MP: CXC chemokines in angiogenesis. Cytokine Growth Factor Rev. 2005, 16: 593-609. 10.1016/j.cytogfr.2005.04.007.CrossRefPubMed
15.
Zurück zum Zitat Yahiaoui L, Villeneuve A, Valderrama-Carvajal H, Burke F, Fixman ED: Endothelin-1 regulates proliferative responses, both alone and synergistically with PDGF, in rat tracheal smooth muscle cells. Cell Physiol Biochem. 2006, 17: 37-46. 10.1159/000091462.CrossRefPubMed Yahiaoui L, Villeneuve A, Valderrama-Carvajal H, Burke F, Fixman ED: Endothelin-1 regulates proliferative responses, both alone and synergistically with PDGF, in rat tracheal smooth muscle cells. Cell Physiol Biochem. 2006, 17: 37-46. 10.1159/000091462.CrossRefPubMed
16.
Zurück zum Zitat Haq A, El-Ramahi K, Al-Dalaan A, Al-Sedairy ST: Serum and synovial fluid concentrations of endothelin-1 in patients with rheumatoid arthritis. J Med. 1999, 30: 51-60.PubMed Haq A, El-Ramahi K, Al-Dalaan A, Al-Sedairy ST: Serum and synovial fluid concentrations of endothelin-1 in patients with rheumatoid arthritis. J Med. 1999, 30: 51-60.PubMed
17.
Zurück zum Zitat Miyasaka N, Hirata Y, Ando K, Sato K, Morita H, Shichiri M, Kanno K, Tomita K, Marumo F: Increased production of endothelin-1 in patients with inflammatory arthritides. Arthritis Rheum. 1992, 35: 397-400. 10.1002/art.1780350406.CrossRefPubMed Miyasaka N, Hirata Y, Ando K, Sato K, Morita H, Shichiri M, Kanno K, Tomita K, Marumo F: Increased production of endothelin-1 in patients with inflammatory arthritides. Arthritis Rheum. 1992, 35: 397-400. 10.1002/art.1780350406.CrossRefPubMed
18.
Zurück zum Zitat Pache M, Schwarz HA, Kaiser HJ, Wuest P, Kloti M, Dubler B, Flammer J: Elevated plasma endothelin-1 levels and vascular dysregulation in patients with rheumatoid arthritis. Med Sci Monit. 2002, 8: CR616-CR619.PubMed Pache M, Schwarz HA, Kaiser HJ, Wuest P, Kloti M, Dubler B, Flammer J: Elevated plasma endothelin-1 levels and vascular dysregulation in patients with rheumatoid arthritis. Med Sci Monit. 2002, 8: CR616-CR619.PubMed
19.
Zurück zum Zitat Nahir AM, Hoffman A, Lorber M, Keiser HR: Presence of immunoreactive endothelin in synovial fluid: analysis of 22 cases. J Rheumatol. 1991, 18: 678-680.PubMed Nahir AM, Hoffman A, Lorber M, Keiser HR: Presence of immunoreactive endothelin in synovial fluid: analysis of 22 cases. J Rheumatol. 1991, 18: 678-680.PubMed
20.
Zurück zum Zitat Bek EL, McMillen MA: Endothelins are angiogenic. J Cardiovasc Pharmacol. 2000, S135-S139. Suppl 1 Bek EL, McMillen MA: Endothelins are angiogenic. J Cardiovasc Pharmacol. 2000, S135-S139. Suppl 1
21.
Zurück zum Zitat Cruz A, Parnot C, Ribatti D, Corvol P, Gasc JM: Endothelin-1, a regulator of angiogenesis in the chick chorioallantoic membrane. J Vasc Res. 2001, 38: 536-545. 10.1159/000051089.CrossRefPubMed Cruz A, Parnot C, Ribatti D, Corvol P, Gasc JM: Endothelin-1, a regulator of angiogenesis in the chick chorioallantoic membrane. J Vasc Res. 2001, 38: 536-545. 10.1159/000051089.CrossRefPubMed
22.
Zurück zum Zitat Salani D, Taraboletti G, Rosano L, Di Castro V, Borsotti P, Giavazzi R, Bagnato A: Endothelin-1 induces an angiogenic phenotype in cultured endothelial cells and stimulates neovascularization in vivo. Am J Pathol. 2000, 157: 1703-1711.PubMedCentralCrossRefPubMed Salani D, Taraboletti G, Rosano L, Di Castro V, Borsotti P, Giavazzi R, Bagnato A: Endothelin-1 induces an angiogenic phenotype in cultured endothelial cells and stimulates neovascularization in vivo. Am J Pathol. 2000, 157: 1703-1711.PubMedCentralCrossRefPubMed
23.
Zurück zum Zitat Bagnato A, Spinella F: Emerging role of endothelin-1 in tumor angiogenesis. Trends Endocrinol Metab. 2003, 14: 44-50. 10.1016/S1043-2760(02)00010-3.CrossRefPubMed Bagnato A, Spinella F: Emerging role of endothelin-1 in tumor angiogenesis. Trends Endocrinol Metab. 2003, 14: 44-50. 10.1016/S1043-2760(02)00010-3.CrossRefPubMed
24.
Zurück zum Zitat Goligorsky MS, Budzikowski AS, Tsukahara H, Noiri E: Co-operation between endothelin and nitric oxide in promoting endothelial cell migration and angiogenesis. Clin Exp Pharmacol Physiol. 1999, 26: 269-271. 10.1046/j.1440-1681.1999.03029.x.CrossRefPubMed Goligorsky MS, Budzikowski AS, Tsukahara H, Noiri E: Co-operation between endothelin and nitric oxide in promoting endothelial cell migration and angiogenesis. Clin Exp Pharmacol Physiol. 1999, 26: 269-271. 10.1046/j.1440-1681.1999.03029.x.CrossRefPubMed
25.
Zurück zum Zitat Pfeifer A, Kessler T, Silletti S, Cheresh DA, Verma IM: Suppression of angiogenesis by lentiviral delivery of PEX, a noncatalytic fragment of matrix metalloproteinase 2. Proc Natl Acad Sci USA. 2000, 97: 12227-12232. 10.1073/pnas.220399597.PubMedCentralCrossRefPubMed Pfeifer A, Kessler T, Silletti S, Cheresh DA, Verma IM: Suppression of angiogenesis by lentiviral delivery of PEX, a noncatalytic fragment of matrix metalloproteinase 2. Proc Natl Acad Sci USA. 2000, 97: 12227-12232. 10.1073/pnas.220399597.PubMedCentralCrossRefPubMed
26.
Zurück zum Zitat Storgard CM, Stupack DG, Jonczyk A, Goodman SL, Fox RI, Cheresh DA: Decreased angiogenesis and arthritic disease in rabbits treated with an alphavbeta3 antagonist. J Clin Invest. 1999, 103: 47-54.PubMedCentralCrossRefPubMed Storgard CM, Stupack DG, Jonczyk A, Goodman SL, Fox RI, Cheresh DA: Decreased angiogenesis and arthritic disease in rabbits treated with an alphavbeta3 antagonist. J Clin Invest. 1999, 103: 47-54.PubMedCentralCrossRefPubMed
27.
Zurück zum Zitat Badger AM, Blake S, Kapadia R, Sarkar S, Levin J, Swift BA, Hoffman SJ, Stroup GB, Miller WH, Gowen M, Lark MW: Disease-modifying activity of SB 27 an orally active, nonpeptide alphavbeta3 (vitronectin receptor) antagonist, in rat adjuvant-induced arthritis. Arthritis Rheum. 3005, 44: 128-137. 10.1002/1529-0131(200101)44:1<128::AID-ANR17>3.0.CO;2-M.CrossRef Badger AM, Blake S, Kapadia R, Sarkar S, Levin J, Swift BA, Hoffman SJ, Stroup GB, Miller WH, Gowen M, Lark MW: Disease-modifying activity of SB 27 an orally active, nonpeptide alphavbeta3 (vitronectin receptor) antagonist, in rat adjuvant-induced arthritis. Arthritis Rheum. 3005, 44: 128-137. 10.1002/1529-0131(200101)44:1<128::AID-ANR17>3.0.CO;2-M.CrossRef
28.
Zurück zum Zitat Gerlag DM, Borges E, Tak PP, Ellerby HM, Bredesen DE, Pasqualini R, Ruoslahti E, Firestein GS: Suppression of murine collagen-induced arthritis by targeted apoptosis of synovial neovasculature. Arthritis Res. 2001, 3: 357-361. 10.1186/ar327.PubMedCentralCrossRefPubMed Gerlag DM, Borges E, Tak PP, Ellerby HM, Bredesen DE, Pasqualini R, Ruoslahti E, Firestein GS: Suppression of murine collagen-induced arthritis by targeted apoptosis of synovial neovasculature. Arthritis Res. 2001, 3: 357-361. 10.1186/ar327.PubMedCentralCrossRefPubMed
29.
Zurück zum Zitat Koch AE, Halloran MM, Haskell CJ, Shah MR, Polverini PJ: Angiogenesis mediated by soluble forms of E-selectin and vascular cell adhesion molecule-1. Nature. 1995, 376: 517-519. 10.1038/376517a0.CrossRefPubMed Koch AE, Halloran MM, Haskell CJ, Shah MR, Polverini PJ: Angiogenesis mediated by soluble forms of E-selectin and vascular cell adhesion molecule-1. Nature. 1995, 376: 517-519. 10.1038/376517a0.CrossRefPubMed
30.
Zurück zum Zitat Halloran MM, Carley WW, Polverini PJ, Haskell CJ, Phan S, Anderson BJ, Woods JM, Campbell PL, Volin MV, Backer AE, et al: Ley/H: an endothelial-selective, cytokine-inducible, angiogenic mediator. J Immunol. 2000, 164: 868-4877.CrossRef Halloran MM, Carley WW, Polverini PJ, Haskell CJ, Phan S, Anderson BJ, Woods JM, Campbell PL, Volin MV, Backer AE, et al: Ley/H: an endothelial-selective, cytokine-inducible, angiogenic mediator. J Immunol. 2000, 164: 868-4877.CrossRef
31.
Zurück zum Zitat Koch AE, Nickoloff BJ, Holgersson J, Seed B, Haines GK, Burrows JC, Leibovich SJ: 4A11, a monoclonal antibody recognizing a novel antigen expressed on aberrant vascular endothelium. Upregulation in an in vivo model of contact dermatitis. Am J Pathol. 1994, 144: 244-259.PubMedCentralPubMed Koch AE, Nickoloff BJ, Holgersson J, Seed B, Haines GK, Burrows JC, Leibovich SJ: 4A11, a monoclonal antibody recognizing a novel antigen expressed on aberrant vascular endothelium. Upregulation in an in vivo model of contact dermatitis. Am J Pathol. 1994, 144: 244-259.PubMedCentralPubMed
32.
Zurück zum Zitat Moses MA, Wiederschain D, Wu I, Fernandez CA, Ghazizadeh V, Lane WS, Flynn E, Sytkowski A, Tao T, Langer R: Troponin I is present in human cartilage and inhibits angiogenesis. Proc Natl Acad Sci USA. 1999, 96: 2645-2650. 10.1073/pnas.96.6.2645.PubMedCentralCrossRefPubMed Moses MA, Wiederschain D, Wu I, Fernandez CA, Ghazizadeh V, Lane WS, Flynn E, Sytkowski A, Tao T, Langer R: Troponin I is present in human cartilage and inhibits angiogenesis. Proc Natl Acad Sci USA. 1999, 96: 2645-2650. 10.1073/pnas.96.6.2645.PubMedCentralCrossRefPubMed
33.
Zurück zum Zitat Matsuno H, Yudoh K, Uzuki M, Nakazawa F, Sawai T, Yamaguchi N, Olsen BR, Kimura T: Treatment with the angiogenesis inhibitor endostatin: a novel therapy in rheumatoid arthritis. J Rheumatol. 2002, 29: 890-895.PubMed Matsuno H, Yudoh K, Uzuki M, Nakazawa F, Sawai T, Yamaguchi N, Olsen BR, Kimura T: Treatment with the angiogenesis inhibitor endostatin: a novel therapy in rheumatoid arthritis. J Rheumatol. 2002, 29: 890-895.PubMed
34.
Zurück zum Zitat Yin G, Liu W, An P, Li P, Ding I, Planelles V, Schwarz EM, Min W: Endostatin gene transfer inhibits joint angiogenesis and pannus formation in inflammatory arthritis. Mol Ther. 2002, 5: 547-554. 10.1006/mthe.2002.0590.CrossRefPubMed Yin G, Liu W, An P, Li P, Ding I, Planelles V, Schwarz EM, Min W: Endostatin gene transfer inhibits joint angiogenesis and pannus formation in inflammatory arthritis. Mol Ther. 2002, 5: 547-554. 10.1006/mthe.2002.0590.CrossRefPubMed
35.
Zurück zum Zitat Ranieri G, Patruno R, Ruggieri E, Montemurro S, Valerio P, Ribatti D: Vascular endothelial growth factor (VEGF) as a target of bevacizumab in cancer: from the biology to the clinic. Curr Med Chem. 2006, 13: 1845-1857. 10.2174/092986706777585059.CrossRefPubMed Ranieri G, Patruno R, Ruggieri E, Montemurro S, Valerio P, Ribatti D: Vascular endothelial growth factor (VEGF) as a target of bevacizumab in cancer: from the biology to the clinic. Curr Med Chem. 2006, 13: 1845-1857. 10.2174/092986706777585059.CrossRefPubMed
36.
Zurück zum Zitat Distler JH, Gay S, Distler O: Angiogenesis and vasculogenesis in systemic sclerosis. Rheumatology (Oxford). 2006, iii26-iii27. 10.1093/rheumatology/kel295. Suppl 3 Distler JH, Gay S, Distler O: Angiogenesis and vasculogenesis in systemic sclerosis. Rheumatology (Oxford). 2006, iii26-iii27. 10.1093/rheumatology/kel295. Suppl 3
37.
Zurück zum Zitat Marczak M, Majewski S, Skopinska-Rozewska E, Polakowski I, Jablonska S: Enhanced angiogenic capability of monocyte-enriched mononuclear cell suspensions from patients with systemic scleroderma. J Invest Dermatol. 1986, 86: 355-358. 10.1111/1523-1747.ep12285572.CrossRefPubMed Marczak M, Majewski S, Skopinska-Rozewska E, Polakowski I, Jablonska S: Enhanced angiogenic capability of monocyte-enriched mononuclear cell suspensions from patients with systemic scleroderma. J Invest Dermatol. 1986, 86: 355-358. 10.1111/1523-1747.ep12285572.CrossRefPubMed
38.
Zurück zum Zitat Kahaleh MB, DeLustro F, Bock W, LeRoy EC: Human monocyte modulation of endothelial cells and fibroblast growth: possible mechanism for fibrosis. Clin Immunol Immunopathol. 1986, 39: 242-255. 10.1016/0090-1229(86)90088-7.CrossRefPubMed Kahaleh MB, DeLustro F, Bock W, LeRoy EC: Human monocyte modulation of endothelial cells and fibroblast growth: possible mechanism for fibrosis. Clin Immunol Immunopathol. 1986, 39: 242-255. 10.1016/0090-1229(86)90088-7.CrossRefPubMed
39.
Zurück zum Zitat Majewski S, Skopinska-Rozewska E, Jablonska S, Polakowski I, Pawinska M, Marczak M, Szmurlo A: Modulatory effect of sera from scleroderma patients on lymphocyte-induced angiogenesis. Arthritis Rheum. 1985, 28: 1133-1139. 10.1002/art.1780281009.CrossRefPubMed Majewski S, Skopinska-Rozewska E, Jablonska S, Polakowski I, Pawinska M, Marczak M, Szmurlo A: Modulatory effect of sera from scleroderma patients on lymphocyte-induced angiogenesis. Arthritis Rheum. 1985, 28: 1133-1139. 10.1002/art.1780281009.CrossRefPubMed
40.
Zurück zum Zitat Konttinen YT, Mackiewicz Z, Ruuttila P, Ceponis A, Sukura A, Povilenaite D, Hukkanen M, Virtanen I: Vascular damage and lack of angiogenesis in systemic sclerosis skin. Clin Rheumatol. 2003, 22: 196-202. 10.1007/s10067-003-0698-1.CrossRefPubMed Konttinen YT, Mackiewicz Z, Ruuttila P, Ceponis A, Sukura A, Povilenaite D, Hukkanen M, Virtanen I: Vascular damage and lack of angiogenesis in systemic sclerosis skin. Clin Rheumatol. 2003, 22: 196-202. 10.1007/s10067-003-0698-1.CrossRefPubMed
41.
Zurück zum Zitat Hebbar M, Peyrat JP, Hornez L, Hatron PY, Hachulla E, Devulder B: Increased concentrations of the circulating angiogenesis inhibitor endostatin in patients with systemic sclerosis. Arthritis Rheum. 2000, 43: 889-893. 10.1002/1529-0131(200004)43:4<889::AID-ANR21>3.0.CO;2-5.CrossRefPubMed Hebbar M, Peyrat JP, Hornez L, Hatron PY, Hachulla E, Devulder B: Increased concentrations of the circulating angiogenesis inhibitor endostatin in patients with systemic sclerosis. Arthritis Rheum. 2000, 43: 889-893. 10.1002/1529-0131(200004)43:4<889::AID-ANR21>3.0.CO;2-5.CrossRefPubMed
42.
Zurück zum Zitat Distler O, Del Rosso A, Giacomelli R, Cipriani P, Conforti ML, Guiducci S, Gay RE, Michel BA, Bruhlmann P, Muller-Ladner U, et al: Angiogenic and angiostatic factors in systemic sclerosis: increased levels of vascular endothelial growth factor are a feature of the earliest disease stages and are associated with the absence of fingertip ulcers. Arthritis Res. 2002, 4: R11-10.1186/ar596.PubMedCentralCrossRefPubMed Distler O, Del Rosso A, Giacomelli R, Cipriani P, Conforti ML, Guiducci S, Gay RE, Michel BA, Bruhlmann P, Muller-Ladner U, et al: Angiogenic and angiostatic factors in systemic sclerosis: increased levels of vascular endothelial growth factor are a feature of the earliest disease stages and are associated with the absence of fingertip ulcers. Arthritis Res. 2002, 4: R11-10.1186/ar596.PubMedCentralCrossRefPubMed
43.
Zurück zum Zitat Macko RF, Gelber AC, Young BA, Lowitt MH, White B, Wigley FM, Goldblum SE: Increased circulating concentrations of the counteradhesive proteins SPARC and thrombospondin-1 in systemic sclerosis (scleroderma). Relationship to platelet and endothelial cell activation. J Rheumatol. 2002, 29: 2565-2570.PubMed Macko RF, Gelber AC, Young BA, Lowitt MH, White B, Wigley FM, Goldblum SE: Increased circulating concentrations of the counteradhesive proteins SPARC and thrombospondin-1 in systemic sclerosis (scleroderma). Relationship to platelet and endothelial cell activation. J Rheumatol. 2002, 29: 2565-2570.PubMed
44.
Zurück zum Zitat Needleman BW, Wigley FM, Stair RW: Interleukin-1, interleukin-2, interleukin-4, interleukin-6, tumor necrosis factor alpha, and interferon-gamma levels in sera from patients with scleroderma. Arthritis Rheum. 1992, 35: 67-72. 10.1002/art.1780350111.CrossRefPubMed Needleman BW, Wigley FM, Stair RW: Interleukin-1, interleukin-2, interleukin-4, interleukin-6, tumor necrosis factor alpha, and interferon-gamma levels in sera from patients with scleroderma. Arthritis Rheum. 1992, 35: 67-72. 10.1002/art.1780350111.CrossRefPubMed
45.
Zurück zum Zitat Dziankowska-Bartkowiak B, Waszczykowska E, Zalewska A, Sysa-Jedrzejowska A: Correlation of endostatin and tissue inhibitor of metalloproteinases 2 (TIMP2) serum levels with cardiovascular involvement in systemic sclerosis patients. Mediators Inflamm. 2005, 3: 144-149. 10.1155/MI.2005.144.CrossRef Dziankowska-Bartkowiak B, Waszczykowska E, Zalewska A, Sysa-Jedrzejowska A: Correlation of endostatin and tissue inhibitor of metalloproteinases 2 (TIMP2) serum levels with cardiovascular involvement in systemic sclerosis patients. Mediators Inflamm. 2005, 3: 144-149. 10.1155/MI.2005.144.CrossRef
46.
Zurück zum Zitat D'Alessio S, Fibbi G, Cinelli M, Guiducci S, Del Rosso A, Margheri F, Serrati S, Pucci M, Kahaleh B, Fan P, et al: Matrix metalloproteinase 12-dependent cleavage of urokinase receptor in systemic sclerosis microvascular endothelial cells results in impaired angiogenesis. Arthritis Rheum. 2004, 50: 3275-3285. 10.1002/art.20562.CrossRefPubMed D'Alessio S, Fibbi G, Cinelli M, Guiducci S, Del Rosso A, Margheri F, Serrati S, Pucci M, Kahaleh B, Fan P, et al: Matrix metalloproteinase 12-dependent cleavage of urokinase receptor in systemic sclerosis microvascular endothelial cells results in impaired angiogenesis. Arthritis Rheum. 2004, 50: 3275-3285. 10.1002/art.20562.CrossRefPubMed
47.
Zurück zum Zitat Giusti B, Serrati S, Margheri F, Papucci L, Rossi L, Poggi F, Magi A, Del Rosso A, Cinelli M, Guiducci S, et al: The antiangiogenic tissue kallikrein pattern of endothelial cells in systemic sclerosis. Arthritis Rheum. 2005, 52: 3618-3628. 10.1002/art.21383.CrossRefPubMed Giusti B, Serrati S, Margheri F, Papucci L, Rossi L, Poggi F, Magi A, Del Rosso A, Cinelli M, Guiducci S, et al: The antiangiogenic tissue kallikrein pattern of endothelial cells in systemic sclerosis. Arthritis Rheum. 2005, 52: 3618-3628. 10.1002/art.21383.CrossRefPubMed
48.
Zurück zum Zitat Del Papa N, Colombo G, Fracchiolla N, Moronetti LM, Ingegnoli F, Maglione W, Comina DP, Vitali C, Fantini F, Cortelezzi A: Circulating endothelial cells as a marker of ongoing vascular disease in systemic sclerosis. Arthritis Rheum. 2004, 50: 1296-1304. 10.1002/art.20116.CrossRefPubMed Del Papa N, Colombo G, Fracchiolla N, Moronetti LM, Ingegnoli F, Maglione W, Comina DP, Vitali C, Fantini F, Cortelezzi A: Circulating endothelial cells as a marker of ongoing vascular disease in systemic sclerosis. Arthritis Rheum. 2004, 50: 1296-1304. 10.1002/art.20116.CrossRefPubMed
49.
Zurück zum Zitat Kuwana M, Okazaki Y, Yasuoka H, Kawakami Y, Ikeda Y: Defective vasculogenesis in systemic sclerosis. Lancet. 2004, 364: 603-610. 10.1016/S0140-6736(04)16853-0.CrossRefPubMed Kuwana M, Okazaki Y, Yasuoka H, Kawakami Y, Ikeda Y: Defective vasculogenesis in systemic sclerosis. Lancet. 2004, 364: 603-610. 10.1016/S0140-6736(04)16853-0.CrossRefPubMed
50.
Zurück zum Zitat Del Papa N, Quirici N, Soligo D, Scavullo C, Cortiana M, Borsotti C, Maglione W, Comina DP, Vitali C, Fraticelli P, et al: Bone marrow endothelial progenitors are defective in systemic sclerosis. Arthritis Rheum. 2006, 54: 2605-2615. 10.1002/art.22035.CrossRefPubMed Del Papa N, Quirici N, Soligo D, Scavullo C, Cortiana M, Borsotti C, Maglione W, Comina DP, Vitali C, Fraticelli P, et al: Bone marrow endothelial progenitors are defective in systemic sclerosis. Arthritis Rheum. 2006, 54: 2605-2615. 10.1002/art.22035.CrossRefPubMed
51.
Zurück zum Zitat Distler O, Pap T, Kowal-Bielecka O, Meyringer R, Guiducci S, Landthaler M, Scholmerich J, Michel BA, Gay RE, Matucci-Cerinic M, et al: Overexpression of monocyte chemoattractant protein 1 in systemic sclerosis: role of platelet-derived growth factor and effects on monocyte chemotaxis and collagen synthesis. Arthritis Rheum. 2001, 44: 2665-2678. 10.1002/1529-0131(200111)44:11<2665::AID-ART446>3.0.CO;2-S.CrossRefPubMed Distler O, Pap T, Kowal-Bielecka O, Meyringer R, Guiducci S, Landthaler M, Scholmerich J, Michel BA, Gay RE, Matucci-Cerinic M, et al: Overexpression of monocyte chemoattractant protein 1 in systemic sclerosis: role of platelet-derived growth factor and effects on monocyte chemotaxis and collagen synthesis. Arthritis Rheum. 2001, 44: 2665-2678. 10.1002/1529-0131(200111)44:11<2665::AID-ART446>3.0.CO;2-S.CrossRefPubMed
52.
Zurück zum Zitat Yamamoto T, Eckes B, Krieg T: High expression and autoinduction of monocyte chemoattractant protein-1 in scleroderma fibroblasts. Eur J Immunol. 2001, 31: 2936-2941. 10.1002/1521-4141(2001010)31:10<2936::AID-IMMU2936>3.0.CO;2-0.CrossRefPubMed Yamamoto T, Eckes B, Krieg T: High expression and autoinduction of monocyte chemoattractant protein-1 in scleroderma fibroblasts. Eur J Immunol. 2001, 31: 2936-2941. 10.1002/1521-4141(2001010)31:10<2936::AID-IMMU2936>3.0.CO;2-0.CrossRefPubMed
53.
Zurück zum Zitat Galindo M, Santiago B, Rivero M, Rullas J, Alcami J, Pablos JL: Chemokine expression by systemic sclerosis fibroblasts: abnormal regulation of monocyte chemoattractant protein 1 expression. Arthritis Rheum. 2001, 44: 1382-1386. 10.1002/1529-0131(200106)44:6<1382::AID-ART231>3.0.CO;2-T.CrossRefPubMed Galindo M, Santiago B, Rivero M, Rullas J, Alcami J, Pablos JL: Chemokine expression by systemic sclerosis fibroblasts: abnormal regulation of monocyte chemoattractant protein 1 expression. Arthritis Rheum. 2001, 44: 1382-1386. 10.1002/1529-0131(200106)44:6<1382::AID-ART231>3.0.CO;2-T.CrossRefPubMed
54.
Zurück zum Zitat Koch AE, Kronfeld-Harrington LB, Szekanecz Z, Cho MM, Haines GK, Harlow LA, Strieter RM, Kunkel SL, Massa MC, Barr WG, et al: In situ expression of cytokines and cellular adhesion molecules in the skin of patients with systemic sclerosis. Their role in early and late disease. Pathobiology. 1993, 61: 239-246.CrossRefPubMed Koch AE, Kronfeld-Harrington LB, Szekanecz Z, Cho MM, Haines GK, Harlow LA, Strieter RM, Kunkel SL, Massa MC, Barr WG, et al: In situ expression of cytokines and cellular adhesion molecules in the skin of patients with systemic sclerosis. Their role in early and late disease. Pathobiology. 1993, 61: 239-246.CrossRefPubMed
55.
Zurück zum Zitat Distler O, Distler JH, Scheid A, Acker T, Hirth A, Rethage J, Michel BA, Gay RE, Muller-Ladner U, Matucci-Cerinic M, et al: Uncontrolled expression of vascular endothelial growth factor and its receptors leads to insufficient skin angiogenesis in patients with systemic sclerosis. Circ Res. 2004, 95: 109-116. 10.1161/01.RES.0000134644.89917.96.CrossRefPubMed Distler O, Distler JH, Scheid A, Acker T, Hirth A, Rethage J, Michel BA, Gay RE, Muller-Ladner U, Matucci-Cerinic M, et al: Uncontrolled expression of vascular endothelial growth factor and its receptors leads to insufficient skin angiogenesis in patients with systemic sclerosis. Circ Res. 2004, 95: 109-116. 10.1161/01.RES.0000134644.89917.96.CrossRefPubMed
56.
Zurück zum Zitat Davies CA, Jeziorska M, Freemont AJ, Herrick AL: The differential expression of VEGF, VEGFR-2, and GLUT-1 proteins in disease subtypes of systemic sclerosis. Hum Pathol. 2006, 37: 190-197. 10.1016/j.humpath.2005.10.007.CrossRefPubMed Davies CA, Jeziorska M, Freemont AJ, Herrick AL: The differential expression of VEGF, VEGFR-2, and GLUT-1 proteins in disease subtypes of systemic sclerosis. Hum Pathol. 2006, 37: 190-197. 10.1016/j.humpath.2005.10.007.CrossRefPubMed
57.
Zurück zum Zitat Choi JJ, Min DJ, Cho ML, Min SY, Kim SJ, Lee SS, Park KS, Seo YI, Kim WU, Park SH, et al: Elevated vascular endothelial growth factor in systemic sclerosis. J Rheumatol. 2003, 30: 1529-1533.PubMed Choi JJ, Min DJ, Cho ML, Min SY, Kim SJ, Lee SS, Park KS, Seo YI, Kim WU, Park SH, et al: Elevated vascular endothelial growth factor in systemic sclerosis. J Rheumatol. 2003, 30: 1529-1533.PubMed
58.
Zurück zum Zitat Allanore Y, Borderie D, Lemarechal H, Ekindjian OG, Kahan A: Nifedipine decreases sVCAM-1 concentrations and oxidative stress in systemic sclerosis but does not affect the concentrations of vascular endothelial growth factor or its soluble receptor 1. Arthritis Res Ther. 2004, 6: R309-R314. 10.1186/ar1183.PubMedCentralCrossRefPubMed Allanore Y, Borderie D, Lemarechal H, Ekindjian OG, Kahan A: Nifedipine decreases sVCAM-1 concentrations and oxidative stress in systemic sclerosis but does not affect the concentrations of vascular endothelial growth factor or its soluble receptor 1. Arthritis Res Ther. 2004, 6: R309-R314. 10.1186/ar1183.PubMedCentralCrossRefPubMed
59.
Zurück zum Zitat Kuryliszyn-Moskal A, Klimiuk PA, Sierakowski S: Soluble adhesion molecules (sVCAM-1, sE-selectin), vascular endothelial growth factor (VEGF) and endothelin-1 in patients with systemic sclerosis: relationship to organ systemic involvement. Clin Rheumatol. 2005, 24: 111-116. 10.1007/s10067-004-0987-3.CrossRefPubMed Kuryliszyn-Moskal A, Klimiuk PA, Sierakowski S: Soluble adhesion molecules (sVCAM-1, sE-selectin), vascular endothelial growth factor (VEGF) and endothelin-1 in patients with systemic sclerosis: relationship to organ systemic involvement. Clin Rheumatol. 2005, 24: 111-116. 10.1007/s10067-004-0987-3.CrossRefPubMed
60.
Zurück zum Zitat Dor Y, Djonov V, Abramovitch R, Itin A, Fishman GI, Carmeliet P, Goelman G, Keshet E: Conditional switching of VEGF provides new insights into adult neovascularization and pro-angiogenic therapy. EMBO J. 2002, 21: 1939-1947. 10.1093/emboj/21.8.1939.PubMedCentralCrossRefPubMed Dor Y, Djonov V, Abramovitch R, Itin A, Fishman GI, Carmeliet P, Goelman G, Keshet E: Conditional switching of VEGF provides new insights into adult neovascularization and pro-angiogenic therapy. EMBO J. 2002, 21: 1939-1947. 10.1093/emboj/21.8.1939.PubMedCentralCrossRefPubMed
61.
Zurück zum Zitat Allanore Y, Borderie D, Airo P, Guiducci S, Czirjak L, Nassonov EL, Riemekasten G, Caramaschi P, Majdan M, Krasowska D, et al: Lack of association between 3 vascular endothelial growth factor gene polymorphisms and systemic sclerosis: results from a multicenter EUSTAR study of European Caucasian patients. Ann Rheum Dis. 2007, 66: 257-259. 10.1136/ard.2006.054346.PubMedCentralCrossRefPubMed Allanore Y, Borderie D, Airo P, Guiducci S, Czirjak L, Nassonov EL, Riemekasten G, Caramaschi P, Majdan M, Krasowska D, et al: Lack of association between 3 vascular endothelial growth factor gene polymorphisms and systemic sclerosis: results from a multicenter EUSTAR study of European Caucasian patients. Ann Rheum Dis. 2007, 66: 257-259. 10.1136/ard.2006.054346.PubMedCentralCrossRefPubMed
62.
Zurück zum Zitat Seibold JR, Matucci-Cerinic M, Denton CP, Furst DE, Mayes MD, Kramer F, Morganti A, Korn JH: Bosentan reduces the number of new digital ulcers in patients with systemic sclerosis. Ann Rheum Dis. 2006, 65: S90- Seibold JR, Matucci-Cerinic M, Denton CP, Furst DE, Mayes MD, Kramer F, Morganti A, Korn JH: Bosentan reduces the number of new digital ulcers in patients with systemic sclerosis. Ann Rheum Dis. 2006, 65: S90-
63.
Zurück zum Zitat Gershwin ME, Abplanalp H, Castles JJ, Ikeda RM, van der Water J, Eklund J, Haynes D: Characterization of a spontaneous disease of white leghorn chickens resembling progressive systemic sclerosis (scleroderma). J Exp Med. 1981, 153: 1640-1659. 10.1084/jem.153.6.1640.CrossRefPubMed Gershwin ME, Abplanalp H, Castles JJ, Ikeda RM, van der Water J, Eklund J, Haynes D: Characterization of a spontaneous disease of white leghorn chickens resembling progressive systemic sclerosis (scleroderma). J Exp Med. 1981, 153: 1640-1659. 10.1084/jem.153.6.1640.CrossRefPubMed
64.
Zurück zum Zitat Gruschwitz MS, Shoenfeld Y, Krupp M, Gershwin ME, Penner E, Brezinschek HP, Wick G: Antinuclear antibody profile in UCD line 200 chickens: a model for progressive systemic sclerosis. Int Arch Allergy Immunol. 1993, 100: 307-313.CrossRefPubMed Gruschwitz MS, Shoenfeld Y, Krupp M, Gershwin ME, Penner E, Brezinschek HP, Wick G: Antinuclear antibody profile in UCD line 200 chickens: a model for progressive systemic sclerosis. Int Arch Allergy Immunol. 1993, 100: 307-313.CrossRefPubMed
65.
Zurück zum Zitat Sgonc R, Wick G: What can we learn from an avian model for scleroderma?. The Decade of Autoimmunity. Edited by: Schoenfeld Y. 1999, Amsterdam, The Netherlands: Elsevier, 209-217.CrossRef Sgonc R, Wick G: What can we learn from an avian model for scleroderma?. The Decade of Autoimmunity. Edited by: Schoenfeld Y. 1999, Amsterdam, The Netherlands: Elsevier, 209-217.CrossRef
66.
Zurück zum Zitat Wick G, Sgonc R, Kroemer G: Autoimmune disease, spontaneous animal models. Encyclopaedia of Immunology. Edited by: Delves PJ, Roitt IM. 1998, London, UK: Academic Press, 280-287.CrossRef Wick G, Sgonc R, Kroemer G: Autoimmune disease, spontaneous animal models. Encyclopaedia of Immunology. Edited by: Delves PJ, Roitt IM. 1998, London, UK: Academic Press, 280-287.CrossRef
67.
Zurück zum Zitat Sgonc R, Gruschwitz MS, Dietrich H, Recheis H, Gershwin ME, Wick G: Endothelial cell apoptosis is a primary pathogenetic event underlying skin lesions in avian and human scleroderma. J Clin Invest. 1996, 98: 785-792.PubMedCentralCrossRefPubMed Sgonc R, Gruschwitz MS, Dietrich H, Recheis H, Gershwin ME, Wick G: Endothelial cell apoptosis is a primary pathogenetic event underlying skin lesions in avian and human scleroderma. J Clin Invest. 1996, 98: 785-792.PubMedCentralCrossRefPubMed
68.
Zurück zum Zitat Sgonc R, Gruschwitz MS, Boeck G, Sepp N, Gruber J, Wick G: Endothelial cell apoptosis in systemic sclerosis is induced by antibody-dependent cell-mediated cytotoxicity via CD95. Arthritis Rheum. 2000, 43: 2550-2562. 10.1002/1529-0131(200011)43:11<2550::AID-ANR24>3.0.CO;2-H.CrossRefPubMed Sgonc R, Gruschwitz MS, Boeck G, Sepp N, Gruber J, Wick G: Endothelial cell apoptosis in systemic sclerosis is induced by antibody-dependent cell-mediated cytotoxicity via CD95. Arthritis Rheum. 2000, 43: 2550-2562. 10.1002/1529-0131(200011)43:11<2550::AID-ANR24>3.0.CO;2-H.CrossRefPubMed
69.
Zurück zum Zitat Worda M, Sgonc R, Dietrich H, Niederegger H, Sundick RS, Gershwin ME, Wick G: In vivo analysis of the apoptosis-inducing effect of anti-endothelial cell antibodies in systemic sclerosis by the chorionallantoic membrane assay. Arthritis Rheum. 2003, 48: 2605-2614. 10.1002/art.11179.CrossRefPubMed Worda M, Sgonc R, Dietrich H, Niederegger H, Sundick RS, Gershwin ME, Wick G: In vivo analysis of the apoptosis-inducing effect of anti-endothelial cell antibodies in systemic sclerosis by the chorionallantoic membrane assay. Arthritis Rheum. 2003, 48: 2605-2614. 10.1002/art.11179.CrossRefPubMed
70.
Zurück zum Zitat Nguyen VA, Sgonc R, Dietrich H, Wick G: Endothelial injury in internal organs of University of California at Davis line 200 (UCD 200) chickens, an animal model for systemic sclerosis (scleroderma). J Autoimmun. 2000, 14: 143-149. 10.1006/jaut.1999.0355.CrossRefPubMed Nguyen VA, Sgonc R, Dietrich H, Wick G: Endothelial injury in internal organs of University of California at Davis line 200 (UCD 200) chickens, an animal model for systemic sclerosis (scleroderma). J Autoimmun. 2000, 14: 143-149. 10.1006/jaut.1999.0355.CrossRefPubMed
71.
Zurück zum Zitat Koch AE: Review: angiogenesis: implications for rheumatoid arthritis. Arthritis Rheum. 1998, 41: 951-962. 10.1002/1529-0131(199806)41:6<951::AID-ART2>3.0.CO;2-D.CrossRefPubMed Koch AE: Review: angiogenesis: implications for rheumatoid arthritis. Arthritis Rheum. 1998, 41: 951-962. 10.1002/1529-0131(199806)41:6<951::AID-ART2>3.0.CO;2-D.CrossRefPubMed
Metadaten
Titel
Vasculopathy and disordered angiogenesis in selected rheumatic diseases: rheumatoid arthritis and systemic sclerosis
verfasst von
Alisa E Koch
Oliver Distler
Publikationsdatum
01.08.2007
Verlag
BioMed Central
Erschienen in
Arthritis Research & Therapy / Ausgabe Sonderheft 2/2007
Elektronische ISSN: 1478-6362
DOI
https://doi.org/10.1186/ar2187

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