Endothelial cell‐derived endothelin‐1 is involved in abnormal scar formation by dermal fibroblasts through RhoA/Rho‐kinase pathway

Kiya, Koichiro; Kubo, Tateki; Kawai, Kenichiro; Matsuzaki, Shinsuke; Maeda, Daisuke; Fujiwara, Toshihiro; Nishibayashi, Akimitsu; Kanazawa, Shigeyuki; Yano, Kenji; Amano, Genki; Katayama, Taiichi; Hosokawa, Ko

doi:10.1111/exd.13264

Cited by 31 publications

(24 citation statements)

References 49 publications

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“…Endothelin-1, a predominant one of three isoforms in humans, is considered a pivotal element in vasoconstriction regulation [9]. Moreover, this peptide exerts a complex fibrogenic effect: directly affects fibroblasts and indirectly stimulates fibrosis by enhancing TGF-β effect [10]. Another molecule which is perceived to participate in endothelial injury is fractalkine.…”

Section: Introductionmentioning

confidence: 99%

Altered serum level of metabolic and endothelial factors in patients with systemic sclerosis

et al. 2019

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Systemic sclerosis (SSc) is a chronic connective tissue disease characterized by progressive fibrosis, vascular impairment and immune abnormalities. In recent years, adipokines (mediators synthetized by adipose tissue) have been indicated as a possible missing link in the pathogenesis of SSc. The aim of this study was to investigate the serum concentration of metabolic adipose tissue factors: adiponectin, resistin, leptin and endothelial proteins: endothelin-1, fractalkine and galectin-3 in patients with systemic sclerosis. The study included 100 patients with confirmed SSc diagnosis and 20 healthy individuals. The concentration of respective proteins was determined by enzyme-linked immunosorbent assay. The following markers showed statistically significant increased mean concentrations in patients with SSc in comparison to healthy control: resistin (13.41 vs 8.54 ng/mL; P = 0.0012), endothelin-1 (1.99 vs 1.31 pg/mL; P = 0.0072) and fractalkine (2.93 vs 1.68 ng/mL; P = 0.0007). Elevated serum levels of galectin-3 (4.54 vs 3.26 ng/mL; P = 0.0672) and leptin (19,542 vs 14,210 pg/mL; P = 0.1817) were observed. Decreased concentration of adiponectin was found in patients with SSc (5150 vs 8847 pg/mL; P = 0.0001). Fractalkine and galectin-3 levels were significantly higher in diffuse cutaneous SSc than limited cutaneous SSc subset (3.93 ng/mL vs 2.58 ng/mL, P = 0.0018; 6.86 ng/mL vs 3.78 ng/mL, P = 0.0008, respectively) and correlated positively with modified Rodnan Skin Score in total SSc patients (r = 0.376, P = 0.0009; r = 0.236, P = 0.018, respectively). In conclusion, an increased serum level of resistin associated with increased endothelin-1 and fractalkine level and decreased adiponectin level may indicate a significant role of the adipose tissue in the development and progression of vascular abnormalities in patients with systemic sclerosis. Fractalkine and galectin-3 may participate in promoting and exacerbating the fibrotic process in SSc.

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Section: Introductionmentioning

confidence: 99%

Altered serum level of metabolic and endothelial factors in patients with systemic sclerosis

et al. 2019

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“…All values in this figure represent the mean ± SD. ** p < 0.01. secrete the latter factor, thereby activating nearby fibroblasts and initiating fibrotic reactions (Kiya et al, 2017;Wang X.Q. et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

“…It is known that during the aberrant wound healing that leads to pathological scarring, VEC proliferation and new blood vessel formation may be shaped by immune and other factors such as endothelin-1, vascular endothelial growth factor, platelet-derived growth factor, and transforming growth factor-β. Notably, VECs may also secrete the latter factor, thereby activating nearby fibroblasts and initiating fibrotic reactions ( Kiya et al, 2017 ; Wang X.Q. et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Gene Expression Profile of Isolated Dermal Vascular Endothelial Cells in Keloids

Matsumoto

Aoki

Okubo

et al. 2020

Front. Cell Dev. Biol.

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Wound healing is a complex biological process, and imbalances of various substances in the wound environment may prolong healing and lead to excessive scarring. Keloid is abnormal proliferation of scar tissue beyond the original wound margins with excessive deposition of extracellular matrix (ECM) and chronic inflammation. Despite numerous previous research efforts, the pathogenesis of keloid remains unknown. Vascular endothelial cells (VECs) are a major type of inductive cell in inflammation and fibrosis. Despite several studies on vascular morphology in keloid formation, there has been no functional analysis of the role of VECs. In the present study, we isolated living VECs from keloid tissues and investigated gene expression patterns using microarray analysis. We obtained 5 keloid tissue samples and 6 normal skin samples from patients without keloid. Immediately after excision, tissue samples were gently minced and living cells were isolated. Magnetic-activated cell sorting of VECs was performed by negative selection of fibroblasts and CD45 + cells and by positive selection of CD31 + cells. After RNA extraction, gene expression analysis was performed to compare VECs isolated from keloid tissue (KVECs) with VECs from normal skin (NVECs). After cell isolation, the percentage of CD31 + cells as measured by flow cytometry ranged from 81.8%-98.6%. Principal component analysis was used to identify distinct molecular phenotypes in KVECs versus NVECs and these were divided into two subgroups. In total, 15 genes were upregulated, and 3 genes were downregulated in KVECs compared with NVECs using the t-test (< 0.05). Quantitative RT-PCR and immunohistochemistry showed 16fold and 11-fold overexpression of SERPINA3 and LAMC2, respectively. SERPINA3 encodes the serine protease inhibitor, α1-antichymotripsin. Laminin γ2-Chain (LAMC2) is a subunit of laminin-5 that induces retraction of vascular endothelial cells and enhances vascular permeability. This is the first report of VEC isolation and gene expression analysis in keloid tissue. Our data suggest that SERPINA3 and LAMC2 upregulation in KVECs may contribute to the development of fibrosis and prolonged inflammation in keloid. Further functional investigation of these genes will help clarify the mechanisms of abnormal scar tissue proliferation.

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“…However, the mechanism of keloid pathogenesis remains unclear. In recent studies, specific factors (Chemokine-like factor-1, [ 15 ] endothelin 1, [ 19 ] and growth/differentiation factor 9 [ 20 ] ), several genes ( p53 [ 21 ] and Stat-3 [ 22 ] ), and various types of human leukocyte antigens (HLAs) [ 23 – 26 ] (HLA-DR5, HLA-DQ23, HLA-DQA1, and HLA-DQB1) were found to be involved. Keloids can easily recur after monotherapy, including surgical excision.…”

Section: Discussionmentioning

confidence: 99%

Hyperbaric oxygen therapy can ameliorate the EMT phenomenon in keloid tissue

et al. 2018

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Background:Hyperbaric oxygen therapy (HBOT) has been widely used in the clinical setting. In this study, HBOT therapy was evaluated for its ability to ameliorate the epithelial-to-mesenchymal transition (EMT) phenomenon in keloid tissue.Methods:Keloid patients were randomly divided into two groups: keloid patients (K group, 9 patients) and keloid patients receiving HBOT (O group, 9 patients). A third group with normal skin (S group, 9 patients) was established for control. Before HBOT and surgery, a laser Doppler flowmeter was used to measure the keloid blood supply of patients in the O group. Hematoxylin and eosin (H&E) staining was used to observe morphology. E-cadherin, ZO-1, vimentin, fibronectin, vascular endothelial growth factor (VEGF), and hypoxia inducible factor (HIF)-1α were measured by immunofluorescence staining and Western blot analysis. Real-time quantitative polymerase chain reaction (RT-qPCR) was used to evaluate the mRNA expression level of these factors as well.Results:In the O group, keloid blood perfusion was significantly reduced after patients received HBOT. Compared with the K group, lower expression levels of vimentin, vibronectin, VEGF, and HIF-1α were observed in the O group, whereas the expression of E-cadherin and ZO-1 was significantly higher. The mRNA expression of E-cadherin and ZO-1 was also increased after HBOT.Conclusions:The expression levels of factors related to the EMT phenomenon were significantly reversed in keloid patients after they received HBOT, indicating that HBOT may be an effective therapy against the EMT phenomenon in keloid patients.

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Endothelial cell‐derived endothelin‐1 is involved in abnormal scar formation by dermal fibroblasts through RhoA/Rho‐kinase pathway

Cited by 31 publications

References 49 publications

Altered serum level of metabolic and endothelial factors in patients with systemic sclerosis

Altered serum level of metabolic and endothelial factors in patients with systemic sclerosis

Gene Expression Profile of Isolated Dermal Vascular Endothelial Cells in Keloids

Hyperbaric oxygen therapy can ameliorate the EMT phenomenon in keloid tissue

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