Rheumatol Int DOI 10.1007/s00296-014-2949-7
Original Article
Increased serum levels of soluble vascular endothelial‑cadherin in patients with systemic vasculitis Tao Chen · Zai‑pei Guo · Na Cao · Sha Qin · Meng‑meng Li · Rui‑zhen Jia
Received: 30 November 2013 / Accepted: 16 January 2014 © Springer-Verlag Berlin Heidelberg 2014
Abstract Henoch–Schönlein purpura (HSP) is a commonest systemic vasculitis (SV) in childhood characterized by an inflammatory reaction directed at vessels. Endothelial damage and perivascular leukocyte infiltrates are vital in the development of HSP. Vascular endothelial (VE)cadherin is an endothelial cell-specific adhesion molecule, which plays critical roles in angiogenesis and endothelial integrity. Herein, we investigated the serum levels of soluble VE-cadherin (sVE-cadherin) in patients with HSP and other forms of SV. The serum levels of sVE-cadherin in 30 patients with HSP, together with patients with urticarial vasculitis, allergic vasculitis, Behcet disease, psoriasis vulgaris (PV) and atopic dermatitis (AD) and 26 health controls were measured by enzyme-linked immunosorbent assay. Serum levels of sVE-cadherin were significantly increased in patients with HSP in acute stage and patients with other forms of SV but not in patients with PV or AD. Moreover, Serum sVE-cadherin levels in HSP patients were correlated with the severity of this disease and serum concentrations of IgA anticardiolipin antibodies and vascular endothelial growth factor. Taken together, we show firstly that serum sVE-cadherin is abnormally increased in HSP patients. Increased serum levels of sVE-cadherin might be T. Chen · Z. Guo (*) · N. Cao · S. Qin · M. Li Department of Dermatovenereology, West China Hospital of Sichuan University, No. 37, Guoxue Alley, Chengdu, Sichuan Province, China e-mail: [email protected] T. Chen Department of Dermatovenereology, Chengdu Second People’s Hospital, Chengdu 610041, Sichuan Province, China R. Jia Open Laboratory, West China Second Hospital of Sichuan University, Chengdu, Sichuan Province, China
a novel biomarker for evaluating the severity of HSP and useful for identifying the presence of SV in inflammatory skin conditions. Keywords Henoch–Schönlein purpura · Soluble vascular endothelial-cadherin · Systemic vasculitis
Introduction Henoch–Schönlein purpura (HSP) is a commonest systemic vasculitis (SV) in childhood with purpuric rash, arthritis, renal involvement and abdominal pain. Endothelial damage and perivascular leukocyte infiltrates are vital in the development of HSP. Although the actual cause and mechanism are not well known, increasing evidence suggest that immune complexes containing IgA predominantly depositing on small vessel wall, activated neutrophils, increased circulating pro-inflammatory cytokines, chemokines and oxidative stress have been implicated as likely candidates [1–6]. The endothelium of blood vessels, serves the major physical barrier in the extravasation of blood components and leukocytes to tissue, is the initial site of inflammatory injury in vasculitis. Normal endothelial barrier integrity is maintained by organized tight and adherens junctions. Vascular endothelial (VE)-cadherin is an endothelial cell-specific adhesion molecule, which plays critical roles in angiogenesis and endothelial integrity. Moreover, it has been reported that activated neutrophils, numerous pro-inflammatory cytokines, chemokines and oxidative stress can increase microvascular permeability by targeting VE-cadherin [7–9]. Several previous studies have indicated that the extracellular domain of VE-cadherin can be released by proteases during apoptosis or inflammatory processes [9, 10]. It suggests that
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Rheumatol Int
the secretion of VE-cadherin may play a role in several biological settings that involve reorganization of adherens junctions [11]. In addition, it has been reported that increased circulating soluble VE-cadherin (sVE-cadherin) levels are associated with the pathogenesis of coronary atherosclerosis, diabetic retinopathy and Behcet disease (BD) [12–14]. In these conditions, endothelial damage is an important physiopathological feature. However, the roles of sVE-cadherin in most types of SV such as HSP, urticarial vasculitis (UV) and allergic vasculitis (AV) are completely unknown. Therefore, in this study, we investigated the serum levels of sVE-cadherin in patients with HSP together with other forms of SV (including UV, AV and BD). Patients with inflammatory skin diseases without vasculitis such as psoriasis vulgaris (PV) and atopic dermatitis (AD) were also enrolled into this study as disease controls. Since it has been reported that high levels of IgA autoantibodies, cytokines, chemokines and growth factors appear to be closely associated with the pathogenesis of HSP [2, 5, 15, 16]. In present study, we also analyzed the potential relationships of serum sVE-cadherin levels with disease severity and the concentrations of IgA anticardiolipin antibody (ACA), vascular endothelial growth factor (VEFG), tumor necrosis factor-α (TNF-α) and CCL5 in patients with HSP.
Materials and methods
together with detailed clinical information are provided in Table 1). All patients and controls were not on drugs 14 days before our study. The activity and severity of HSP were assessed by using a clinical scoring system according to our previous report [6]. In 16 patients with HSP, who were treated with oral antihistamines and vitamin C, we collected the sera in acute stage and convalescent stage [18]. All sera were stored at −80 °C until use. Assay for serum sVE‑cadherin, ACA‑IgA, VEGF, TNF‑α and CCL5 levels Serum levels of sVE-cadherin (Bender MedSystems, Vienna, Austria), ACA-IgA, VEGF, TNF-α and CCL5 (R&D Systems Inc., Minneapolis, MN, USA) were quantitated with commercially available enzyme-linked immunosorbent assay (ELISA) kits according to the manufacturer’s instructions. Statistical analysis All results are expressed as mean ± SD. Serum sVE-cadherin differences between groups were determined according to Mann–Whitney U test. Serum sVE-cadherin in HSP patients were compared between acute stage and convalescent stage using Wilcoxon signed ranks test. Correlation coefficients were obtained by Spearman test. P 0.05).
Discussion As described above, the adhesion molecule VE-cadherin, acts as a gatekeeper, plays essential roles in endothelial barrier integrity and the passage of leukocytes. Moreover, it has been recognized that the release of sVE-cadherin represents a signal for the proteolysis of VE-cadherin protein. In this study, we displayed for the first time that serum levels of sVE-cadherin were increased in acute stage of patients with HSP and restored to normal levels in convalescent stage. We also indicated that sVE-cadherin serum levels were correlated with the severity of HSP. SV comprises a wide spectrum of diseases that affect the blood vessels. Etiologically, SV can be classified as a primary phenomenon, such as HSP, UV, AV or BD or as a secondary disorder (a manifestation of infection, adverse drug eruption, malignancies or connective tissue diseases). Despite the different causes such as vascular deposition of immune complexes or activation by infection, the common pathophysiological feature is endothelial damage and perivascular leukocyte infiltrates. In addition, the release of sVE-cadherin by endothelial cells is associated with endothelial apoptosis or inflammatory response [9, 10]. Hence, it would be plausible to propose that like HSP, patients with other forms of SV may also have
valescent stage a Positive correlations were found between serum sVE-cadherin levels and overall clinical scores (b) in 30 HSP patients by Spearman tests
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Rheumatol Int
Fig. 2 Serum soluble vascular endothelial-cadherin (sVE-cadherin) levels in HSP patients were correlated with the serum concentrations of IgA anti-endothelial cell antibodies (a) and VEFG (b). However,
no correlations were determined between serum levels of sVE-cadherin and TNF-α (c) or CCL5 (d)
increased sVE-cadherin serum levels. Previously, Habibagahi et al. [14] reported that serum sVE-cadherin levels in BD patients were significantly higher than those in healthy controls. Similarly, our data demonstrated that patients with other forms of SV (including UV, AV and BD) besides HSP have increased serum sVE-cadherin levels. As described above, patients with coronary atherosclerosis and diabetic retinopathy also have high serum levels of sVE-cadherin [12, 13]. It seems that serum sVE-cadherin levels are not a specific marker of SV. In addition, our results also indicated that serum levels of sVE-cadherin were no changes in patients with inflammatory skin diseases without vasculitis, including PV and AD. Therefore, we suggest that serum levels of sVE-cadherin might be useful for identifying the presence of SV in inflammatory skin conditions. In this study, we also demonstrated that serum sVEcadherin levels correlated with the concentrations of ACAIgA and VEGF in HSP patients. Previous studies suggested that ACA-IgA is closely related to the production of IgA immune complexes and the development of vasculitis in
HSP [19]. On the other hand, it has been noted that VEGF, as a potent permeability, chemotactic, and migratory factor is associated with the morphological and functional changes of the vascular bed and inflammatory reaction in HSP [16]. Moreover, a direct role of VEGF on sVE-cadherin release in endothelial cells has been reported [20]. Given these findings above, we speculate that ACA-IgA and VEGF may play some roles in the proteolysis of VEcadherin protein and contribute to the development of HSP. Taken together, this study provides first observations on the changes of serum sVE-cadherin levels in patients with HSP and other forms of SV (including UV and AV). We also showed the association of sVE-cadherin with disease severity and serum levels of ACA-IgA and VEGF in HSP patients. The proteolysis of VE-cadherin protein might be an important physiopathological feature and implicated in the pathogenesis of HSP and other forms of SV. A limitation of our study was the relatively small sample size. Although our results have significant implications, further research with large sample size is still needed.
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Rheumatol Int Acknowledgments The study was supported, in part, by Natural Science Foundation of China (81101198 and 81271752). Conflict of interest None.
References 1. Linskey KR, Kroshinsky D, Mihm MC Jr, Hoang MP (2012) Immunoglobulin-A associated small-vessel vasculitis: a 10 year experience at the Massachusetts General Hospital. J Am Acad Dermatol 66:813–822 2. Del Vecchio GC, Penza R, Altomare M, Piacente L, Aceto G, Lassandro G et al (2008) Cytokine pattern and endothelium damage markers in Henoch–Schönlein purpura. Immunopharmacol Immunotoxicol 30:623–629 3. Chen T, Jia RZ, Guo ZP, Cao N, Li MM, Jiao XY (2013) Elevated serum interleukin-33 levels in patients with Henoch–Schönlein purpura. Arch Dermatol Res 305:173–177 4. Chen T, Guo ZP, Li MM, Li JY, Jiao XY, Zhang YH et al (2011) Tumour necrosis factor-like weak inducer of apoptosis (TWEAK), an important mediator of endothelial inflammation, is associated with the pathogenesis of Henoch–Schönlein purpura. Clin Exp Immunol 166:64–71 5. Chen T, Guo ZP, Jiao XY, Jia RZ, Zhang YH, Li JY et al (2011) CCL5, CXCL16, and CX3CL1 are associated with Henoch– Schönlein purpura. Arch Dermatol Res 303:715–725 6. Chen T, Guo ZP, Zhang YH, Gao Y, Liu HJ, Li JY (2011) Elevated serum heme oxygenase-1 and insulin-like growth factor-1 levels in patients with Henoch–Schönlein purpura. Rheumatol Int 31:321–326 7. Petreaca ML, Yao M, Liu Y, Defea K, Martins-Green M (2007) Transactivation of vascular endothelial growth factor receptor-2 by interleukin-8 (IL-8/CXCL8) is required for IL-8/CXCL8induced endothelial permeability. Mol Biol Cell 18:5014–5023 8. Alexander JS, Alexander BC, Eppihimer LA, Goodyear N, Haque R, Davis CP (2000) Inflammatory mediators induce sequestration of VE-cadherin in cultured human endothelial cells. Inflammation 24:99–113 9. Sidibé A, Mannic T, Arboleas M, Subileau M, Gulino-Debrac D, Bouillet L et al (2012) Soluble VE-cadherin in rheumatoid arthritis patients correlates with disease activity: evidence for tumor necrosis factor α-induced VE-cadherin cleavage. Arthritis Rheum 64:77–87
10. Herren B, Levkau B, Raines EW, Ross R (1998) Cleavage of beta-catenin and plakoglobin and shedding of VE-cadherin during endothelial apoptosis: evidence for a role for caspases and metalloproteinases. Mol Biol Cell 9:1589–1601 11. Schulz B, Pruessmeyer J, Maretzky T, Ludwig A, Blobel CP, Saftig P et al (2008) ADAM10 regulates endothelial permeability and T-cell transmigration by proteolysis of vascular endothelial cadherin. Circ Res 102:1192–1201 12. Soeki T, Tamura Y, Shinohara H, Sakabe K, Onose Y, Fukuda N (2004) Elevated concentration of soluble vascular endothelial cadherin is associated with coronary atherosclerosis. Circ J 68:1–5 13. Abu El-Asrar AM, Nawaz MI, Kangave D, Abouammoh M, Mohammad G (2012) High-mobility group box-1 and endothelial cell angiogenic markers in the vitreous from patients with proliferative diabetic retinopathy. Mediat Inflamm 2012:697489 14. Habibagahi Z, Habibagahi M, Heidari M (2010) Raised concentration of soluble form of vascular endothelial cadherin and IL-23 in sera of patients with Behcet’s disease. Mod Rheumatol 20:154–159 15. Kawakami T, Watabe H, Mizoguchi M, Soma Y (2006) Elevated serum IgA anticardiolipin antibody levels in adult Henoch– Schönlein purpura. Br J Dermatol 155:983–987 16. Topaloglu R, Sungur A, Baskin E, Besbas N, Saatci U, Bakkaloglu A (2001) Vascular endothelial growth factor in Henoch– Schönlein purpura. J Rheumatol 28:2269–2273 17. Mills JA, Michel BA, Bloch DA, Calabrese LH, Hunder GG, Arend WP et al (1990) The American College of Rheumatology 1990 criteria for the classification of Henoch–Schönlein purpura. Arthritis Rheum 33:1114–1121 18. Yang YH, Wang SJ, Chuang YH, Lin YT, Chiang BL (2002) The level of IgA antibodies to human umbilical vein endothelial cells can be enhanced by TNF-alpha treatment in children with Henoch–Schönlein purpura. Clin Exp Immunol 130:352–357 19. Kawakami T, Yamazaki M, Mizoguchi M, Soma Y (2008) High titer of serum antiphospholipid antibody levels in adult Henoch– Schönlein purpura and cutaneous leukocytoclastic angiitis. Arthritis Rheum 59:561–567 20. Villasante A, Pacheco A, Ruiz A, Pellicer A, Garcia-Velasco JA (2007) Vascular endothelial cadherin regulates vascular permeability: implications for ovarian hyperstimulation syndrome. J Clin Endocrinol Metab 92:314–321
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Original Article
Increased serum levels of soluble vascular endothelial‑cadherin in patients with systemic vasculitis Tao Chen · Zai‑pei Guo · Na Cao · Sha Qin · Meng‑meng Li · Rui‑zhen Jia
Received: 30 November 2013 / Accepted: 16 January 2014 © Springer-Verlag Berlin Heidelberg 2014
Abstract Henoch–Schönlein purpura (HSP) is a commonest systemic vasculitis (SV) in childhood characterized by an inflammatory reaction directed at vessels. Endothelial damage and perivascular leukocyte infiltrates are vital in the development of HSP. Vascular endothelial (VE)cadherin is an endothelial cell-specific adhesion molecule, which plays critical roles in angiogenesis and endothelial integrity. Herein, we investigated the serum levels of soluble VE-cadherin (sVE-cadherin) in patients with HSP and other forms of SV. The serum levels of sVE-cadherin in 30 patients with HSP, together with patients with urticarial vasculitis, allergic vasculitis, Behcet disease, psoriasis vulgaris (PV) and atopic dermatitis (AD) and 26 health controls were measured by enzyme-linked immunosorbent assay. Serum levels of sVE-cadherin were significantly increased in patients with HSP in acute stage and patients with other forms of SV but not in patients with PV or AD. Moreover, Serum sVE-cadherin levels in HSP patients were correlated with the severity of this disease and serum concentrations of IgA anticardiolipin antibodies and vascular endothelial growth factor. Taken together, we show firstly that serum sVE-cadherin is abnormally increased in HSP patients. Increased serum levels of sVE-cadherin might be T. Chen · Z. Guo (*) · N. Cao · S. Qin · M. Li Department of Dermatovenereology, West China Hospital of Sichuan University, No. 37, Guoxue Alley, Chengdu, Sichuan Province, China e-mail: [email protected] T. Chen Department of Dermatovenereology, Chengdu Second People’s Hospital, Chengdu 610041, Sichuan Province, China R. Jia Open Laboratory, West China Second Hospital of Sichuan University, Chengdu, Sichuan Province, China
a novel biomarker for evaluating the severity of HSP and useful for identifying the presence of SV in inflammatory skin conditions. Keywords Henoch–Schönlein purpura · Soluble vascular endothelial-cadherin · Systemic vasculitis
Introduction Henoch–Schönlein purpura (HSP) is a commonest systemic vasculitis (SV) in childhood with purpuric rash, arthritis, renal involvement and abdominal pain. Endothelial damage and perivascular leukocyte infiltrates are vital in the development of HSP. Although the actual cause and mechanism are not well known, increasing evidence suggest that immune complexes containing IgA predominantly depositing on small vessel wall, activated neutrophils, increased circulating pro-inflammatory cytokines, chemokines and oxidative stress have been implicated as likely candidates [1–6]. The endothelium of blood vessels, serves the major physical barrier in the extravasation of blood components and leukocytes to tissue, is the initial site of inflammatory injury in vasculitis. Normal endothelial barrier integrity is maintained by organized tight and adherens junctions. Vascular endothelial (VE)-cadherin is an endothelial cell-specific adhesion molecule, which plays critical roles in angiogenesis and endothelial integrity. Moreover, it has been reported that activated neutrophils, numerous pro-inflammatory cytokines, chemokines and oxidative stress can increase microvascular permeability by targeting VE-cadherin [7–9]. Several previous studies have indicated that the extracellular domain of VE-cadherin can be released by proteases during apoptosis or inflammatory processes [9, 10]. It suggests that
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Rheumatol Int
the secretion of VE-cadherin may play a role in several biological settings that involve reorganization of adherens junctions [11]. In addition, it has been reported that increased circulating soluble VE-cadherin (sVE-cadherin) levels are associated with the pathogenesis of coronary atherosclerosis, diabetic retinopathy and Behcet disease (BD) [12–14]. In these conditions, endothelial damage is an important physiopathological feature. However, the roles of sVE-cadherin in most types of SV such as HSP, urticarial vasculitis (UV) and allergic vasculitis (AV) are completely unknown. Therefore, in this study, we investigated the serum levels of sVE-cadherin in patients with HSP together with other forms of SV (including UV, AV and BD). Patients with inflammatory skin diseases without vasculitis such as psoriasis vulgaris (PV) and atopic dermatitis (AD) were also enrolled into this study as disease controls. Since it has been reported that high levels of IgA autoantibodies, cytokines, chemokines and growth factors appear to be closely associated with the pathogenesis of HSP [2, 5, 15, 16]. In present study, we also analyzed the potential relationships of serum sVE-cadherin levels with disease severity and the concentrations of IgA anticardiolipin antibody (ACA), vascular endothelial growth factor (VEFG), tumor necrosis factor-α (TNF-α) and CCL5 in patients with HSP.
Materials and methods
together with detailed clinical information are provided in Table 1). All patients and controls were not on drugs 14 days before our study. The activity and severity of HSP were assessed by using a clinical scoring system according to our previous report [6]. In 16 patients with HSP, who were treated with oral antihistamines and vitamin C, we collected the sera in acute stage and convalescent stage [18]. All sera were stored at −80 °C until use. Assay for serum sVE‑cadherin, ACA‑IgA, VEGF, TNF‑α and CCL5 levels Serum levels of sVE-cadherin (Bender MedSystems, Vienna, Austria), ACA-IgA, VEGF, TNF-α and CCL5 (R&D Systems Inc., Minneapolis, MN, USA) were quantitated with commercially available enzyme-linked immunosorbent assay (ELISA) kits according to the manufacturer’s instructions. Statistical analysis All results are expressed as mean ± SD. Serum sVE-cadherin differences between groups were determined according to Mann–Whitney U test. Serum sVE-cadherin in HSP patients were compared between acute stage and convalescent stage using Wilcoxon signed ranks test. Correlation coefficients were obtained by Spearman test. P 0.05).
Discussion As described above, the adhesion molecule VE-cadherin, acts as a gatekeeper, plays essential roles in endothelial barrier integrity and the passage of leukocytes. Moreover, it has been recognized that the release of sVE-cadherin represents a signal for the proteolysis of VE-cadherin protein. In this study, we displayed for the first time that serum levels of sVE-cadherin were increased in acute stage of patients with HSP and restored to normal levels in convalescent stage. We also indicated that sVE-cadherin serum levels were correlated with the severity of HSP. SV comprises a wide spectrum of diseases that affect the blood vessels. Etiologically, SV can be classified as a primary phenomenon, such as HSP, UV, AV or BD or as a secondary disorder (a manifestation of infection, adverse drug eruption, malignancies or connective tissue diseases). Despite the different causes such as vascular deposition of immune complexes or activation by infection, the common pathophysiological feature is endothelial damage and perivascular leukocyte infiltrates. In addition, the release of sVE-cadherin by endothelial cells is associated with endothelial apoptosis or inflammatory response [9, 10]. Hence, it would be plausible to propose that like HSP, patients with other forms of SV may also have
valescent stage a Positive correlations were found between serum sVE-cadherin levels and overall clinical scores (b) in 30 HSP patients by Spearman tests
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Rheumatol Int
Fig. 2 Serum soluble vascular endothelial-cadherin (sVE-cadherin) levels in HSP patients were correlated with the serum concentrations of IgA anti-endothelial cell antibodies (a) and VEFG (b). However,
no correlations were determined between serum levels of sVE-cadherin and TNF-α (c) or CCL5 (d)
increased sVE-cadherin serum levels. Previously, Habibagahi et al. [14] reported that serum sVE-cadherin levels in BD patients were significantly higher than those in healthy controls. Similarly, our data demonstrated that patients with other forms of SV (including UV, AV and BD) besides HSP have increased serum sVE-cadherin levels. As described above, patients with coronary atherosclerosis and diabetic retinopathy also have high serum levels of sVE-cadherin [12, 13]. It seems that serum sVE-cadherin levels are not a specific marker of SV. In addition, our results also indicated that serum levels of sVE-cadherin were no changes in patients with inflammatory skin diseases without vasculitis, including PV and AD. Therefore, we suggest that serum levels of sVE-cadherin might be useful for identifying the presence of SV in inflammatory skin conditions. In this study, we also demonstrated that serum sVEcadherin levels correlated with the concentrations of ACAIgA and VEGF in HSP patients. Previous studies suggested that ACA-IgA is closely related to the production of IgA immune complexes and the development of vasculitis in
HSP [19]. On the other hand, it has been noted that VEGF, as a potent permeability, chemotactic, and migratory factor is associated with the morphological and functional changes of the vascular bed and inflammatory reaction in HSP [16]. Moreover, a direct role of VEGF on sVE-cadherin release in endothelial cells has been reported [20]. Given these findings above, we speculate that ACA-IgA and VEGF may play some roles in the proteolysis of VEcadherin protein and contribute to the development of HSP. Taken together, this study provides first observations on the changes of serum sVE-cadherin levels in patients with HSP and other forms of SV (including UV and AV). We also showed the association of sVE-cadherin with disease severity and serum levels of ACA-IgA and VEGF in HSP patients. The proteolysis of VE-cadherin protein might be an important physiopathological feature and implicated in the pathogenesis of HSP and other forms of SV. A limitation of our study was the relatively small sample size. Although our results have significant implications, further research with large sample size is still needed.
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Rheumatol Int Acknowledgments The study was supported, in part, by Natural Science Foundation of China (81101198 and 81271752). Conflict of interest None.
References 1. Linskey KR, Kroshinsky D, Mihm MC Jr, Hoang MP (2012) Immunoglobulin-A associated small-vessel vasculitis: a 10 year experience at the Massachusetts General Hospital. J Am Acad Dermatol 66:813–822 2. Del Vecchio GC, Penza R, Altomare M, Piacente L, Aceto G, Lassandro G et al (2008) Cytokine pattern and endothelium damage markers in Henoch–Schönlein purpura. Immunopharmacol Immunotoxicol 30:623–629 3. Chen T, Jia RZ, Guo ZP, Cao N, Li MM, Jiao XY (2013) Elevated serum interleukin-33 levels in patients with Henoch–Schönlein purpura. Arch Dermatol Res 305:173–177 4. Chen T, Guo ZP, Li MM, Li JY, Jiao XY, Zhang YH et al (2011) Tumour necrosis factor-like weak inducer of apoptosis (TWEAK), an important mediator of endothelial inflammation, is associated with the pathogenesis of Henoch–Schönlein purpura. Clin Exp Immunol 166:64–71 5. Chen T, Guo ZP, Jiao XY, Jia RZ, Zhang YH, Li JY et al (2011) CCL5, CXCL16, and CX3CL1 are associated with Henoch– Schönlein purpura. Arch Dermatol Res 303:715–725 6. Chen T, Guo ZP, Zhang YH, Gao Y, Liu HJ, Li JY (2011) Elevated serum heme oxygenase-1 and insulin-like growth factor-1 levels in patients with Henoch–Schönlein purpura. Rheumatol Int 31:321–326 7. Petreaca ML, Yao M, Liu Y, Defea K, Martins-Green M (2007) Transactivation of vascular endothelial growth factor receptor-2 by interleukin-8 (IL-8/CXCL8) is required for IL-8/CXCL8induced endothelial permeability. Mol Biol Cell 18:5014–5023 8. Alexander JS, Alexander BC, Eppihimer LA, Goodyear N, Haque R, Davis CP (2000) Inflammatory mediators induce sequestration of VE-cadherin in cultured human endothelial cells. Inflammation 24:99–113 9. Sidibé A, Mannic T, Arboleas M, Subileau M, Gulino-Debrac D, Bouillet L et al (2012) Soluble VE-cadherin in rheumatoid arthritis patients correlates with disease activity: evidence for tumor necrosis factor α-induced VE-cadherin cleavage. Arthritis Rheum 64:77–87
10. Herren B, Levkau B, Raines EW, Ross R (1998) Cleavage of beta-catenin and plakoglobin and shedding of VE-cadherin during endothelial apoptosis: evidence for a role for caspases and metalloproteinases. Mol Biol Cell 9:1589–1601 11. Schulz B, Pruessmeyer J, Maretzky T, Ludwig A, Blobel CP, Saftig P et al (2008) ADAM10 regulates endothelial permeability and T-cell transmigration by proteolysis of vascular endothelial cadherin. Circ Res 102:1192–1201 12. Soeki T, Tamura Y, Shinohara H, Sakabe K, Onose Y, Fukuda N (2004) Elevated concentration of soluble vascular endothelial cadherin is associated with coronary atherosclerosis. Circ J 68:1–5 13. Abu El-Asrar AM, Nawaz MI, Kangave D, Abouammoh M, Mohammad G (2012) High-mobility group box-1 and endothelial cell angiogenic markers in the vitreous from patients with proliferative diabetic retinopathy. Mediat Inflamm 2012:697489 14. Habibagahi Z, Habibagahi M, Heidari M (2010) Raised concentration of soluble form of vascular endothelial cadherin and IL-23 in sera of patients with Behcet’s disease. Mod Rheumatol 20:154–159 15. Kawakami T, Watabe H, Mizoguchi M, Soma Y (2006) Elevated serum IgA anticardiolipin antibody levels in adult Henoch– Schönlein purpura. Br J Dermatol 155:983–987 16. Topaloglu R, Sungur A, Baskin E, Besbas N, Saatci U, Bakkaloglu A (2001) Vascular endothelial growth factor in Henoch– Schönlein purpura. J Rheumatol 28:2269–2273 17. Mills JA, Michel BA, Bloch DA, Calabrese LH, Hunder GG, Arend WP et al (1990) The American College of Rheumatology 1990 criteria for the classification of Henoch–Schönlein purpura. Arthritis Rheum 33:1114–1121 18. Yang YH, Wang SJ, Chuang YH, Lin YT, Chiang BL (2002) The level of IgA antibodies to human umbilical vein endothelial cells can be enhanced by TNF-alpha treatment in children with Henoch–Schönlein purpura. Clin Exp Immunol 130:352–357 19. Kawakami T, Yamazaki M, Mizoguchi M, Soma Y (2008) High titer of serum antiphospholipid antibody levels in adult Henoch– Schönlein purpura and cutaneous leukocytoclastic angiitis. Arthritis Rheum 59:561–567 20. Villasante A, Pacheco A, Ruiz A, Pellicer A, Garcia-Velasco JA (2007) Vascular endothelial cadherin regulates vascular permeability: implications for ovarian hyperstimulation syndrome. J Clin Endocrinol Metab 92:314–321
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