Serum Tie2 levels: clinical association with microangiopathies in patients with systemic sclerosis

Noda, Shinichi; Asano, Yoshihide; Aozasa, Naohiko; Akamata, Kaname; Yamada, Daisuke; Masui, Yuri; Tamaki, Zenshiro; Kadono, Takafumi; Sato, Shinichi

doi:10.1111/j.1468-3083.2011.04012.x

Cited by 14 publications

(8 citation statements)

References 19 publications

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“…However, apart from discrepancies that might arise from studying such a heterogeneous disease, these differences might also be attributed to the use of plasma [32] instead of serum. Similar to our observations, the serum levels of sTie2 were found to be elevated by Noda et al [17] and Dunne et al [32], however, the latter study only demonstrating significant differences in the lcSSc subgroup. The study by Gerlicz et al showed a trend towards higher levels of sTie2 in both SSc subsets compared with healthy controls, yet the data were not statistically significant [33].…”

Section: Discussionsupporting

confidence: 92%

“…In contrast to mbTie2, little is known about soluble Tie2 (sTie2), the extracellular domain of the Tie2 receptor, which is released by proteolytic cleavage by matrix metalloproteases upon stimulation with VEGF in a process also referred to as shedding [13, 14]. sTie2 is detectable in healthy individuals, and increased serum concentrations were measured in cardiovascular diseases, diabetic retinopathy [15], and SSc [16, 17]. …”

Section: Introductionmentioning

confidence: 99%

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Tie2 as a novel key factor of microangiopathy in systemic sclerosis

et al. 2017

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BackgroundThe angiopoietin(Ang)/Tie2 system is a key regulator of vascular biology. The expression of membrane bound (mb) Tie2 and Ang-1 ensures vessel stability, whereas Ang-2, inducible by vascular endothelial growth factor (VEGF), hypoxia, and inflammation, acts as an antagonist. Tie2 signalling is also attenuated by soluble Tie2 (sTie2), the extracellular domain of the receptor, which is shed upon stimulation with VEGF. Herein, we investigate the role of Ang/Tie2 in the peripheral vasculopathy in systemic sclerosis (SSc) including animal models.MethodsThe expression of Ang-1/-2 and Tie2 in skin/serum of SSc patients was compared with healthy controls by immunohistochemistry (IHC)/ELISA. Expression of Ang/Tie2 was analysed in different animal models: VEGF transgenic (tg) mice, hypoxia model, bleomycin-induced skin fibrosis, and tight skin 1 (TSK1) mice.ResultsIn SSc, dermal microvessels abundantly expressed Ang-2, but not Ang-1 compared with healthy controls. The percentage of mbTie2+ microvessels was profoundly decreased whereas the levels of sTie2 were increased already in early disease. Both in skin and sera of SSc patients, the Ang1/2 ratio was reduced, being lowest in patients with digital ulcers indicating vessel destabilizing conditions. We next studied potential influencing factors in animal models. The VEGF tg mouse model, the hypoxia, and the inflammation-dependent bleomycin model all showed a similar dysregulation of Ang/Tie2 as in SSc, which did not apply for the non-inflammatory TSK1 model.ConclusionPeripheral microvasculopathy in SSc results from a complex dysregulation of angiogenic signalling networks including the VEGF and the Ang/Tie2 system. The profoundly disturbed Ang-/Tie-2 balance might represent an important target for vascular therapeutic approaches in SSc.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-017-1304-2) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Tie2 as a novel key factor of microangiopathy in systemic sclerosis

et al. 2017

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“…In the replication cohort, sera was also taken at rest from the forearm, in the morning, and stored locally before shipment to our laboratory, in the days after the patient meeting. Serum levels of eight endothelial factors that have been shown to be implicated in SSc (VEGF, placenta growth factor (PlGF), sVCAM, angiopoietin-2, endoglin, endostatin, endothelin-1 and Tie-2) were measured by using the quantitative sandwich enzyme-linked immunosorbent assay (ELISA) technique (Quantikine kits; R&D systems) [11-14,17,18,26-28]. No patient in our cohort had regular alcohol consumption, which has been reported to have an important influence on serum levels of VEGF.…”

Section: Methodsmentioning

confidence: 99%

Correlations between angiogenic factors and capillaroscopic patterns in systemic sclerosis

et al. 2013

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IntroductionWe sought to assess whether nailfold videocapillaroscopy (NVC) patterns are associated with levels of angiogenic factors in systemic sclerosis (SSc).MethodsCirculating endothelial progenitor cells (EPCs) and circulating endothelial cells (CECs) were measured in the peripheral blood of 60 consecutive SSc patients. Serum levels of eight endothelial markers were measured first in these 60 patients, and then in an independent replication cohort of 43 SSc patients in case of association with NVC patterns. NVC patterns were determined by four independent investigators blinded to vascular markers.ResultsPatients with the late-NVC pattern exhibited lower EPC levels (P < 0.0001) and higher VEGF levels (P = 0.03). Higher VEGF levels were confirmed to be associated with the late-NVC pattern in the replication cohort (P = 0.01). By multivariate analysis focused on biomarkers, lower EPC (P = 0.03) and higher VEGF levels (P = 0.001) were independently associated with the late-NVC pattern. In an alternate multivariate model including these two factors and SSc-related disease characteristics, lower EPC counts (P = 0.005), higher VEGF levels (P = 0.01), a history of digital ulcers (P = 0.04), and a modified Rodnan skin score > 14 (P < 0.0001) were independently associated with the late-NVC pattern.ConclusionOur data revealed decreased EPC counts and increased VEGF levels in patients with the late-NVC pattern. Further studies are now needed to determine the role of VEGF and EPCs in endothelial injury and repair in SSc.

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“…Furthermore, increased Ang-2 strongly correlated with skin and lung involvement as well as with disease activity and digital ulcers. In 2011, Noda et al [18] reported no significant difference of Tie-2 levels in both SSc patients and healthy controls. However, in their study, after adjustment of the cut-off value based on the data of normal controls, 27% of SSc patients did show elevated serum Tie-2 levels and Tie-2 correlated with pulmonary arterial hypertension.…”

Section: Discussionmentioning

confidence: 99%

Disturbed Balance between Serum Levels of Receptor Tyrosine Kinases Tie-1, Tie-2 and Angiopoietins in Systemic Sclerosis

Gerlicz

Dziankowska‐Bartkowiak

Dziankowska-Zaborszczyk

et al. 2014

Dermatology

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Objective: The aim of this study was to determine the characteristic factors for vascular development and maintenance levels as well as correlation between Tie-1 receptors, Tie-2 receptors and the corresponding ligands - angiopoietins - in systemic sclerosis (SSc) patients. Materials and Methods: Serum levels of Tie-1, Tie-2, Ang-1 and Ang-2 were measured in 25 SSc patients and healthy controls. Results: There was a statistically significant difference in serum Tie-1 (p = 0.009) and Ang-2 (p = 0.001) levels in SSc patients compared with healthy controls. Significant correlations between Tie-1 and Tie-2 (ρ = 0.70, p = 0.0001) and between Tie-1 and Ang-2 (ρ = -0.92, p = 0.002) were found in the SSc group. Serum levels of Tie-2 were positively associated with esophagus changes (U = 2.03, p = 0.041) and Ang-1 was negatively correlated with duration of Raynaud's phenomenon (ρ = -0.75, p = 0.00008). Conclusion: The increase in serum concentration of Tie-1 and Ang-2 in patients with SSc may confirm a molecular imbalance between receptor tyrosine kinases Tie and their ligands.

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Serum Tie2 levels: clinical association with microangiopathies in patients with systemic sclerosis

Cited by 14 publications

References 19 publications

Tie2 as a novel key factor of microangiopathy in systemic sclerosis

Tie2 as a novel key factor of microangiopathy in systemic sclerosis

Correlations between angiogenic factors and capillaroscopic patterns in systemic sclerosis

Disturbed Balance between Serum Levels of Receptor Tyrosine Kinases Tie-1, Tie-2 and Angiopoietins in Systemic Sclerosis

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