Characterization of microparticles in patients with venous malformations of the head and neck

Zhu, Junyi; Ren, Jian‐Gang; Zhang, Wei; Wang, Fengqin; Cai, Yu; Zhao, Jianhua; Chen, Gang; Zhao, Yi‐Fang

doi:10.1111/odi.12585

Cited by 7 publications

(8 citation statements)

References 60 publications

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“…Ultrastructural analyses of VM lesions in the VM mouse model and patient biopsies showed a disorganized fibrillar collagen matrix and basement membrane ( BM ) abnormalities that may reflect increased in vitro expression of ADAMTS peptidases and plasminogen activators ( tPA , uPA ) that degrade ECM proteins and activate matrix metalloproteinases for ECM remodelling. Fluid from VM lesions and cultures of retrovirally transduced VM mutation HUVEC s (J. Kangas and L. Eklund, unpublished) contain an increased amount of cell shed microparticles, whose importance for VM pathogenesis is currently unknown. (C) Schematic representation of TIE 2‐ VM (left) and normal TIE 2/ ANG signalling (right) in EC s. In normal EC s, extracellular angiopoietin ligands induce TIE 2 translocation and activation in specific subcellular domains in EC – EC and EC – ECM contact sites to regulate vascular stability and motility .…”

Section: Molecular and Cellular Pathology Of Vmsmentioning

confidence: 99%

“…Another potential biomarker that can be measured from the blood or serum is PDGF ‐ B, which is consistently downregulated in different models and clinical samples, including VM mutant‐transduced ECs, genetic VM mouse model, tissue biopsies and serum from VM patients . It has also been recently shown that the peripheral blood of VM patients contains more cell ‐ derived microparticles than similar samples of healthy controls . The number of microparticles is higher if the sample is taken directly from the lesional fluid and correlates with the size of the lesion.…”

Section: Vm Biomarkersmentioning

confidence: 99%

“…In addition, the mRNA and microRNA content of these microparticles differs significantly from that of the healthy controls. The exact function or importance of microparticles is unknown, but they could represent the parent cell they are budded from and therefore provide a molecular readout of VM ECs . ANG2, a context ‐ dependent antagonistic ligand of TIE2 induced in vascular remodelling and EC activation, is another Akt/FOXO1‐dependent gene strongly downregulated in VM HUVECs .…”

Section: Vm Biomarkersmentioning

confidence: 99%

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Development of Molecular Therapies for Venous Malformations

Kangas

Nätynki

Eklund

2018

Basic Clin Pharma Tox

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Vascular anomalies are localized defects of morphogenesis that can affect lymphatic and blood vessels. They are generally called birthmarks, typically observed soon after birth and occurring in up to 10% of children. Based on their clinical and histological characteristics, they are classified into vascular tumours and vascular malformations. The most common malformations are venous malformations (VMs) resulting in chronic vascular diseases that can be associated with significant morbidity necessitating often demanding and repeating clinical management. The current treatment is based on surgical resection and sclerotherapy, which can be impossible due to the size or location of lesions or ineffective due to the regrowth of malformed vessels. Therefore, medical therapies for VMs are highly desired. Recent studies have identified genetic defects that result in the constantly active endothelial cell receptor tyrosine kinase TIE2/phosphoinositide 3-kinase PI3K signalling pathway as a frequent cause for VMs. The first treatment to inhibit this pathway with sirolimus indicated that molecular treatment can be effective against VMs. In addition, certain VM 'hotspot' mutations have been previously found in tumours, providing the rationale for the exploration and repurposing of existing and investigational cancer drugs for VMs. Finally, discoveries of molecular and cellular abnormalities that characterize a large proportion of VMs and the generation of pre-clinical VM mouse models provide the necessary basis for the development of the targeted molecular treatment strategies we discuss in this MiniReview.

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Section: Molecular and Cellular Pathology Of Vmsmentioning

confidence: 99%

Section: Vm Biomarkersmentioning

confidence: 99%

Section: Vm Biomarkersmentioning

confidence: 99%

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Development of Molecular Therapies for Venous Malformations

Kangas

Nätynki

Eklund

2018

Basic Clin Pharma Tox

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“…Following 3 washes with PBS, the cells were fixed in 4% paraformaldehyde in PBS for 20 min at 37˚C, washed 3 times with PBS for 5 min and permeabilized with 0.2% Triton X-100 for 10 min at room temperature. The cells were blocked with 0.5% bovine serum albumin for 1 h at 37˚C, prior to being incubated with monoclonal mouse antibodies against RT-qPCR were performed as previously described (18). Briefly, total RNA was extracted from OKC fibroblasts using TRIzol reagent (Invitrogen; Thermo Fisher Scientific, Inc.…”

Section: Characterization Of Cfmps By Dynamic Light Scatteringmentioning

confidence: 99%

Lymphocyte‑derived microparticles stimulate osteoclastogenesis by inducing RANKL in fibroblasts of odontogenic keratocysts

et al. 2018

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Leukocyte-derived microparticles (LMPs) include neutrophil-, lymphocyte-and monocyte-derived MPs. LMPs act as proinflammatory mediators in autoimmune diseases, infectious diseases and vascular diseases. The present study examined the hypothesis that the percentage of LMPs was increased in patients with inflamed odontogenic keratocysts (OKCs), and investigated the biological effects of Jurkat cell-derived MPs on the fibroblasts of OKCs in vitro. Cyst fluid MPs, obtained by centrifugation of samples from 20 patients with inflamed OKCs, 3 patients with uninflamed OKCs, 15 patients with radicular cysts (RCs) and 12 patients with inflamed dentigerous cysts (DCs), were analyzed by transmission electron microscopy, dynamic light scattering and immunofluorescence staining. The percentages and concentrations of cyst fluid LMPs were further determined by flow cytometry. The cytokine levels of apoptotic Jurkat cell-derived MPs and Jurkat cell supernatants were compared by cytokine antibody arrays. Fibroblasts were isolated from 3 patients with OKC and co-cultured with apoptotic Jurkat cell-derived MPs with or without interleukin (IL)-15Rα to detect the levels of matrix metallopeptidase 9 (MMP-9) and receptor activator of nuclear factor-κB ligand (RANKL) by reverse transcription-quantitative polymerase chain reaction and enzyme-linked immunosorbent assay. The supernatant from Jurkat MPs-treated fibroblasts was collected to make conditioned medium in which the osteoclastogenesis of Raw264.7 cells was determined. Antibodies against human soluble (s)RANKL were added to the conditioned medium to investigate the inhibitory effects. Mean percentages of lymphocyte-and neutrophil-derived MPs were significantly higher in inflamed OKCs than in DCs. Significant elevations in IL-15 were detected in apoptotic Jurkat cell-derived MPs compared with that in Jurkat cell supernatant. Furthermore, higher levels of MMP-9 and RANKL were detected in Jurkat cell MP-treated OKC fibroblasts, and this was partially blocked by IL-15Rα. Increased osteoclast-like cell formation was observed in the Jurkat MPs-treated fibroblast supernatant and Raw264.7 co-culture groups. The anti-human sRANKL antibody in the Jurkat MPs-treated fibroblast supernatant group decreased the osteoclastogenesis of the Raw264.7 cells. These results indicate that LMPs serve as novel communication tools that contribute toward the bone resorption of inflamed OKCs by inducing RANKL of OKC fibroblasts via IL-15.

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“…2 Expansion of VM lesions can cause various complications, including disfigurement, pain, bleeding and obstruction of vital structures. 3 Clinically, sclerotherapy, alone or in combination with surgery, is the mainstay therapy modality for VM, and bleomycin is widely used to treat VM as an effective sclerosant. 4 However, current treatment options are rarely curative and regrowth is common.…”

Section: Introductionmentioning

confidence: 99%

Downregulation of lysyl oxidase in venous malformations: Association with vascular destabilization and sclerotherapy

Zhu

Shao

Guo

et al. 2020

The Journal of Dermatology

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Venous malformations (VM) are localized defects in vascular morphogenesis manifested by dilated venous channels with reduced perivascular cell coverage. As a vital enzyme for extracellular matrix (ECM) deposition, lysyl oxidase (LOX) plays important roles in vascular development and diseases. However, the expression and significance of LOX are unknown in VM. Herein, 22 VM specimens and eight samples of normal skin tissues were evaluated immunohistochemically for the expression of LOX, α-smooth muscle cell actin (α-SMA) and transforming growth factor-β (TGF-β). In vitro studies on human umbilical vein endothelial cells (HUVEC) were employed for determining potential mechanisms. Our results showed that LOX expression was significantly reduced in VM compared with normal skin tissues, in parallel with attenuated perivascular α-SMA + cell coverage and TGF-β downregulation in VM. Further correlation analysis indicated that LOX expression was positively correlated with perivascular α-SMA + cell coverage and TGF-β expression in VM. Moreover, marked elevation of LOX, TGF-β and α-SMA was observed in bleomycin-treated VM samples. Furthermore, our in vitro data demonstrated that both recombinant TGF-β and bleomycin induced obvious increase of LOX expression and activity and a concomitant increase in ECM components in HUVEC, which could be reversed by LOX inhibition. To our best knowledge, this study revealed for the first time the downregulation of LOX in VM and its correlation with vascular destabilization and TGF-β-induced endothelial ECM deposition. Moreover, our results highlighted that LOX may be implicated in the sclerotherapy of VM and holds promise as a therapeutic target.

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Characterization of microparticles in patients with venous malformations of the head and neck

Abstract: This study demonstrates for the first time that patients with VM have an altered MP profile and MP may be associated with VM-associated thrombogenesis. Further studies are required to explore the precise pathophysiological roles of MP in VM.

Cited by 7 publications

References 60 publications

Development of Molecular Therapies for Venous Malformations

Development of Molecular Therapies for Venous Malformations

Lymphocyte‑derived microparticles stimulate osteoclastogenesis by inducing RANKL in fibroblasts of odontogenic keratocysts

Downregulation of lysyl oxidase in venous malformations: Association with vascular destabilization and sclerotherapy

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