Aspergillus fumigatus inhibits angiogenesis through the production of gliotoxin and other secondary metabolites

AbstractIn susceptible hosts, angioinvasion by Aspergillus fumigatus triggers thrombosis, hypoxia, and proinflammatory cytokine release, all of which are stimuli for angiogenesis. We sought to determine whether A fumigatus directly modulates angiogenesis. A fumigatus culture filtrates profoundly inhibited the differentiation, migration, and capillary tube formation of human umbilical vein endothelial cells in vitro. To measure angiogenesis at the site of infection, we devised an in vivo Matrigel assay in cyclophosphamide-treated BALB/c mice with cutaneous invasive aspergillosis. Angiogenesis was significantly suppressed in Matrigel plugs implanted in A fumigatus–infected mice compared with plugs from uninfected control mice. The antiangiogenic effect of A fumigatus was completely abolished by deletion of the global regulator of secondary metabolism, laeA, and to a lesser extent by deletion of gliP, which controls gliotoxin production. Moreover, pure gliotoxin potently inhibited angiogenesis in vitro in a dose-dependent manner. Finally, overexpression of multiple angiogenesis mediator–encoding genes was observed in the lungs of cortisone-treated mice during early invasive aspergillosis, whereas gene expression returned rapidly to baseline levels in cyclophosphamide/cortisone-treated mice. Taken together, these results indicate that suppression of angiogenesis by A fumigatus both in vitro and in a neutropenic mouse model is mediated through secondary metabolite production.

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Topical Application of Hyaluronic Acid-RGD Peptide-Coated Gelatin/Epigallocatechin-3 Gallate (EGCG) Nanoparticles Inhibits Corneal Neovascularization via Inhibition of VEGF Production

Pharmaceutics ◽

10.3390/pharmaceutics12050404 ◽

2020 ◽

Vol 12 (5) ◽

pp. 404 ◽

Cited By ~ 1

Author(s):

Takuya Miyagawa ◽

Zhi-Yu Chen ◽

Che-Yi Chang ◽

Ko-Hua Chen ◽

Yang-Kao Wang ◽

...

Keyword(s):

Hyaluronic Acid ◽

Topical Application ◽

Umbilical Vein ◽

Corneal Neovascularization ◽

Tube Formation ◽

Antiangiogenic Effect ◽

Arginine Glycine Aspartic Acid ◽

Umbilical Vein Endothelial Cells

Neovascularization (NV) of the cornea disrupts vision which leads to blindness. Investigation of antiangiogenic, slow-release and biocompatible approaches for treating corneal NV is of great importance. We designed an eye drop formulation containing gelatin/epigallocatechin-3-gallate (EGCG) nanoparticles (NPs) for targeted therapy in corneal NV. Gelatin-EGCG self-assembled NPs with hyaluronic acid (HA) coating on its surface (named GEH) and hyaluronic acid conjugated with arginine-glycine-aspartic acid (RGD) (GEH-RGD) were synthesized. Human umbilical vein endothelial cells (HUVECs) were used to evaluate the antiangiogenic effect of GEH-RGD NPs in vitro. Moreover, a mouse model of chemical corneal cauterization was employed to evaluate the antiangiogenic effects of GEH-RGD NPs in vivo. GEH-RGD NP treatment significantly reduced endothelial cell tube formation and inhibited metalloproteinase (MMP)-2 and MMP-9 activity in HUVECs in vitro. Topical application of GEH-RGD NPs (once daily for a week) significantly attenuated the formation of pathological vessels in the mouse cornea after chemical cauterization. Reduction in both vascular endothelial growth factor (VEGF) and MMP-9 protein in the GEH-RGD NP-treated cauterized corneas was observed. These results confirm the molecular mechanism of the antiangiogenic effect of GEH-RGD NPs in suppressing pathological corneal NV.

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Accutin, a New Disintegrin, Inhibits Angiogenesis In Vitro and In Vivo by Acting as Integrin vβ3 Antagonist and Inducing Apoptosis

Blood ◽

10.1182/blood.v92.9.3268 ◽

1998 ◽

Vol 92 (9) ◽

pp. 3268-3276 ◽

Cited By ~ 90

Author(s):

Chia Hsin Yeh ◽

Hui-Chin Peng ◽

Tur-Fu Huang

Keyword(s):

Endothelial Cells ◽

Umbilical Vein ◽

Fluorescein Isothiocyanate ◽

Adenosine Diphosphate ◽

Tube Formation ◽

Platelet Glycoprotein ◽

Dependent Manner ◽

Antiangiogenic Effect

Abstract Endothelial integrins play an essential role in angiogenesis and cell survival. Accutin, a new member of disintegrin family derived from venom of Agkistrodon acutus, potently inhibited human platelet aggregation caused by various agonists (eg, thrombin, collagen, and, adenosine diphosphate [ADP]) through the blockade of fibrinogen binding to platelet glycoprotein IIb/IIIa (ie, integrin IIbβ3). In this report, we describe that accutin specifically inhibited the binding of monoclonal antibody (MoAb) 7E3, which recognizes integrin vβ3, to human umbilical vein endothelial cells (HUVECs), but not those of other anti-integrin MoAbs such as 2β1, 3β1, and 5β1. Moreover, accutin, but not the control peptide GRGES, dose-dependently inhibited the 7E3 interaction with HUVECs. Both 7E3 and GRGDS, but not GRGES or Integrelin, significantly blocked fluorescein isothiocyanate-conjugated accutin binding to HUVEC. In functional studies, accutin exhibited inhibitory effects on HUVEC adhesion to immobilized fibrinogen, fibronectin and vitronectin, and the capillary-like tube formation on Matrigel in a dose- and RGD-dependent manner. In addition, it exhibited an effective antiangiogenic effect in vivo when assayed by using the 10-day-old embryo chick CAM model. Furthermore, it potently induced HUVEC apoptotic DNA fragmentation as examined by electrophoretic and flow cytometric assays. In conclusion, accutin inhibits angiogenesis in vivo and in vitro by blocking integrin vβ3 of endothelial cells and by inducing apoptosis. The antiangiogenic activity of disintegrins might be explored as the target of developing the potential antimetastatic agents. © 1998 by The American Society of Hematology.

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Role of Glial Cell Line-Derived Neurotrophic Factor in Adipose Tissue Extract-Induced Angiogenesis in Mice

10.21203/rs.3.rs-1081227/v1 ◽

2021 ◽

Author(s):

Renpeng Zhou ◽

Chuang Yin ◽

Weiwei Bian ◽

Chen Wang

Keyword(s):

Skin Graft ◽

Umbilical Vein ◽

Skin Condition ◽

Tube Formation ◽

Vascular Density ◽

Dependent Manner ◽

Dermal Thickness ◽

Umbilical Vein Endothelial Cells

Abstract Our present study is aimed to evaluate the effects of adipose-derived extracts (AT-Ex) and GDNF within the extracts on skin graft. AT-Ex was harvest from fresh human lipoaspirates with centrifugation, emulsification and lysing by cycles of freeze and thawing. Concentrations of GDNF, VEGF and bFGF were detected by ELISA. AT-Ex and anti-GDNF-antibody-coupled AT-Ex were further used to test their ability to promote tube formation using human umbilical vein endothelial cells (HUVECs) and stimulate angiogenesis in nude skin-graft models. The results demonstrated that abundant GDNF, VEGF and bFGF were detected in AT-Ex, with GDNF displaying the highest concentration. AT-Ex significantly promoted the tube formation ability of HUVECs in vitro, with a dosage-dependent manner, while this ability was partially impaired when the anti-GDNF antibody was conjugated. In vivo, The AT-Ex treatment increased dermal thickness, augmented dermal proliferation and increased vascular density and GDNF contributed greatly to the AT-Ex effect in improvement the grafted skin condition by promoting angiogenesis in vivo. Our results suggested that critical effect of GDNF from AT-Ex on improvement skin graft condition.

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ErMiao San Inhibits Angiogenesis in Rheumatoid Arthritis by Suppressing JAK/STAT Signaling Pathways

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2020/4381212 ◽

2020 ◽

Vol 2020 ◽

pp. 1-12

Author(s):

Lianhua He ◽

Qingxia Qin ◽

Juan He ◽

Han Wang ◽

Yiping Hu ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Ex Vivo ◽

Umbilical Vein ◽

Tube Formation ◽

Antiangiogenic Effect ◽

Necrosis Factor Alpha ◽

Umbilical Vein Endothelial Cells ◽

Sprout Formation

ErMiao San (EMS) is composed of the Cortex Phellodendri chinensis and Atractylodes lancea, and it has the function of eliminating heat and excreting dampness in terms of traditional Chinese medicine to damp heat syndrome. Previous reports indicate that EMS possesses anti-inflammatory activity; however, its action on angiogenesis of rheumatoid arthritis (RA) has not been clarified. The present study aims to determine the antiangiogenic activity of EMS in collagen-induced arthritis (CIA) mice and in various angiogenesis models. Our data showed that EMS (5 g/kg) markedly reduced the immature blood vessels in synovial membrane tissues of inflamed joints from CIA mice. It also inhibited vascular endothelial growth factor (VEGF)-induced microvessel sprout formation ex vivo. Meanwhile, EMS suppressed VEGF-induced migration, invasion, adhesion, and tube formation of human umbilical vein endothelial cells (HUVECs). Moreover, EMS significantly reduced the expression of angiogenic activators including interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha (TNF-α) in synovium of CIA mice. More interestingly, EMS blocked the autophosphorylation of VEGF-induced JAK1, STAT1, and STAT6 in CIA mice and VEGF-induced HUVECs. These findings suggest for the first time that EMS possesses the antiangiogenic effect in RA in vivo, ex vivo, and in vitro by interrupting the targeting of JAK/STAT activation.

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Accutin, a New Disintegrin, Inhibits Angiogenesis In Vitro and In Vivo by Acting as Integrin vβ3 Antagonist and Inducing Apoptosis

Blood ◽

10.1182/blood.v92.9.3268.421k41_3268_3276 ◽

1998 ◽

Vol 92 (9) ◽

pp. 3268-3276 ◽

Cited By ~ 1

Author(s):

Chia Hsin Yeh ◽

Hui-Chin Peng ◽

Tur-Fu Huang

Keyword(s):

Endothelial Cells ◽

Umbilical Vein ◽

Fluorescein Isothiocyanate ◽

Adenosine Diphosphate ◽

Tube Formation ◽

Platelet Glycoprotein ◽

Dependent Manner ◽

Antiangiogenic Effect

Endothelial integrins play an essential role in angiogenesis and cell survival. Accutin, a new member of disintegrin family derived from venom of Agkistrodon acutus, potently inhibited human platelet aggregation caused by various agonists (eg, thrombin, collagen, and, adenosine diphosphate [ADP]) through the blockade of fibrinogen binding to platelet glycoprotein IIb/IIIa (ie, integrin IIbβ3). In this report, we describe that accutin specifically inhibited the binding of monoclonal antibody (MoAb) 7E3, which recognizes integrin vβ3, to human umbilical vein endothelial cells (HUVECs), but not those of other anti-integrin MoAbs such as 2β1, 3β1, and 5β1. Moreover, accutin, but not the control peptide GRGES, dose-dependently inhibited the 7E3 interaction with HUVECs. Both 7E3 and GRGDS, but not GRGES or Integrelin, significantly blocked fluorescein isothiocyanate-conjugated accutin binding to HUVEC. In functional studies, accutin exhibited inhibitory effects on HUVEC adhesion to immobilized fibrinogen, fibronectin and vitronectin, and the capillary-like tube formation on Matrigel in a dose- and RGD-dependent manner. In addition, it exhibited an effective antiangiogenic effect in vivo when assayed by using the 10-day-old embryo chick CAM model. Furthermore, it potently induced HUVEC apoptotic DNA fragmentation as examined by electrophoretic and flow cytometric assays. In conclusion, accutin inhibits angiogenesis in vivo and in vitro by blocking integrin vβ3 of endothelial cells and by inducing apoptosis. The antiangiogenic activity of disintegrins might be explored as the target of developing the potential antimetastatic agents.© 1998 by The American Society of Hematology.

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SiRNA Directed Against Annexin II Receptor Inhibits Angiogenesis via Suppressing MMP2 and MMP9 Expression

Cellular Physiology and Biochemistry ◽

10.1159/000369745 ◽

2015 ◽

Vol 35 (3) ◽

pp. 875-884 ◽

Cited By ~ 16

Author(s):

Hongyuan Song ◽

Dongyan Pan ◽

Weifeng Sun ◽

Cao Gu ◽

Yuelu Zhang ◽

...

Keyword(s):

Matrix Metalloproteinase ◽

Umbilical Vein ◽

Tube Formation ◽

Annexin Ii ◽

Mmp9 Expression ◽

Cell Arrest ◽

Umbilical Vein Endothelial Cells

Background/Aims: Annexin II receptor (AXIIR) is able to mediate Annexin II signal and induce apoptosis, but its role in angiogenesis remains unclear. This study tries to investigate the role of AXIIR in angiogenesis and the plausible molecular mechanism. Methods/Results: RNA interference technology was used to silence AXIIR, and the subsequent effects in vitro and in vivo were evaluated thereafter. Our data indicated that human umbilical vein endothelial cells (HUVECs) expressed AXIIR and knockdown of AXIIR significantly inhibited HUVECs proliferation, adhesion, migration, and tube formation in vitro and suppressed angiogenesis in vivo. Furthermore, AXIIR siRNA induced cell arrest in the S/G2 phase while had no effect on cell apoptosis. We found that these subsequent effects might be via suppressing the expression of matrix metalloproteinase 2and matrix metalloproteinase 9. Conclusion: AXIIR participates in angiogenesis, and may be a potential therapeutic target for angiogenesis related diseases.

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Novel Nargenicin A1 Analog Inhibits Angiogenesis by Downregulating the Endothelial VEGF/VEGFR2 Signaling and Tumoral HIF-1α/VEGF Pathway

Biomedicines ◽

10.3390/biomedicines8080252 ◽

2020 ◽

Vol 8 (8) ◽

pp. 252

Author(s):

Jang Mi Han ◽

Ye Seul Choi ◽

Dipesh Dhakal ◽

Jae Kyung Sohng ◽

Hye Jin Jung

Keyword(s):

Capillary Tube ◽

Umbilical Vein ◽

Hypoxia Inducible Factor ◽

Chorioallantoic Membrane ◽

Tube Formation ◽

Ags Cells ◽

Vegf Pathway ◽

Vegfr2 Signaling

Targeting angiogenesis is an attractive strategy for the treatment of angiogenesis-related diseases, including cancer. We previously identified 23-demethyl 8,13-deoxynargenicin (compound 9) as a novel nargenicin A1 analog with potential anticancer activity. In this study, we investigated the antiangiogenic activity and mode of action of compound 9. This compound was found to effectively inhibit in vitro angiogenic characteristics, including the proliferation, invasion, capillary tube formation, and adhesion of human umbilical vein endothelial cells (HUVECs) stimulated by vascular endothelial growth factor (VEGF). Furthermore, compound 9 suppressed the neovascularization of the chorioallantoic membrane of growing chick embryos in vivo. Notably, the antiangiogenic properties of compound 9 were related to the downregulation of VEGF/VEGFR2-mediated downstream signaling pathways, as well as matrix metalloproteinase (MMP)-2 and MMP-9 expression in HUVECs. In addition, compound 9 was found to decrease the in vitro AGS gastric cancer cell-induced angiogenesis of HUVECs by blocking hypoxia-inducible factor-1α (HIF-1α) and VEGF expression in AGS cells. Collectively, our findings demonstrate for the first time that compound 9 is a promising antiangiogenic agent targeting both VEGF/VEGFR2 signaling in ECs and HIF-1α/VEGF pathway in tumor cells.

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Apigenin Suppresses Angiogenesis by Inhibiting Tube Formation and Inducing Apoptosis

Natural Product Communications ◽

10.1177/1934578x1601101005 ◽

2016 ◽

Vol 11 (10) ◽

pp. 1934578X1601101

Author(s):

Hyun Ju Kim ◽

Mok-Ryeon Ahn

Keyword(s):

Umbilical Vein ◽

Chorioallantoic Membrane ◽

Tube Formation ◽

Anticancer Activities ◽

Apoptotic Pathway ◽

Inhibition Of Angiogenesis ◽

Induced Apoptosis ◽

Umbilical Vein Endothelial Cells

Apigenin has been reported to exert angiogenic and anticancer activities in vitro. The mechanism of inhibition of angiogenesis by apigenin, however, has not been well-established. In this study, we investigated whether apigenin not only inhibited tube formation but also induced apoptosis in human umbilical vein endothelial cells (HUVECs). Furthermore, strong antiangiogenic activity of apigenin was observed in the in vivo assay using chick embryo chorioallantoic membrane (CAM). We also analyzed changes in survival signals and the apoptotic pathway through Western blotting. The results indicate that apigenin exerts its antiangiogenic effects through induction of endothelial apoptosis.

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Dasatinib increases endothelial permeability leading to pleural effusion

European Respiratory Journal ◽

10.1183/13993003.01096-2017 ◽

2018 ◽

Vol 51 (1) ◽

pp. 1701096 ◽

Cited By ~ 16

Author(s):

Carole Phan ◽

Etienne-Marie Jutant ◽

Ly Tu ◽

Raphaël Thuillet ◽

Andrei Seferian ◽

...

Keyword(s):

Pleural Effusion ◽

Kinase Inhibitor ◽

Umbilical Vein ◽

Endothelial Permeability ◽

Cell Junctions ◽

Dependent Manner ◽

Vascular Endothelial ◽

Umbilical Vein Endothelial Cells

Pleural effusion is a frequent side-effect of dasatinib, a second-generation tyrosine kinase inhibitor used in the treatment of chronic myelogenous leukaemia. However, the underlying mechanisms remain unknown. We hypothesised that dasatinib alters endothelial integrity, resulting in increased pulmonary vascular endothelial permeability and pleural effusion.To test this, we established the first animal model of dasatinib-related pleural effusion, by treating rats with a daily regimen of high doses of dasatinib (10 mg·kg−1·day−1 for 8 weeks).Pleural ultrasonography revealed that rats chronically treated with dasatinib developed pleural effusion after 5 weeks. Consistent with these in vivo observations, dasatinib led to a rapid and reversible increase in paracellular permeability of human pulmonary endothelial cell monolayers as reflected by increased macromolecule passage, loss of vascular endothelial cadherin and zonula occludens-1 from cell–cell junctions, and the development of actin stress fibres. These results were replicated using human umbilical vein endothelial cells and confirmed by decreased endothelial resistance. Interestingly, we demonstrated that this increased endothelial permeability is a reactive oxygen species (ROS)-dependent mechanism in vitro and in vivo using a cotreatment with an antioxidant agent, N-acetylcysteine.This study shows that dasatinib alters pulmonary endothelial permeability in a ROS-dependent manner in vitro and in vivo leading to pleural effusion.

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BMSC-Derived Exosomal miR-29a Promotes Angiogenesis and Osteogenesis

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2020.608521 ◽

2020 ◽

Vol 8 ◽

Author(s):

Guo-dong Lu ◽

Peng Cheng ◽

Ting Liu ◽

Zhong Wang

Keyword(s):

Umbilical Vein ◽

Tube Formation ◽

Bone Modeling ◽

Potential Therapeutic Target ◽

Tightly Coupled ◽

Direct Target ◽

Umbilical Vein Endothelial Cells ◽

Bone Modeling And Remodeling

Angiogenesis and osteogenesis are tightly coupled during bone modeling and remodeling processes. Here we reported that bone marrow mesenchymal stem cell (BMSC)-derived exosomal miR-29a promotes angiogenesis and osteogenesis in vitro and in vivo. BMSC-derived exosomes (BMSCs-Exos) can be taken up by human umbilical vein endothelial cells (HUVECs) and promote the proliferation, migration, and tube formation of HUVECs. MiRNA-29a level was high in BMSCs-Exos and can be transported into HUVECs to regulate angiogenesis. VASH1 was identified as a direct target of miR-29a, mediating the effects of BMSC-derived exosomal miR-29a on angiogenesis. More interestingly, miR29a-loaded exosomes from engineered BMSCs (miR-29a-loaded BMSCs-Exos) showed a robust ability of promoting angiogenesis and osteogenesis in vivo. Taken together, these findings suggest that BMSC-derived exosomal miR-29a regulates angiogenesis and osteogenesis, and miR-29a-loaded BMSCs-Exos may serve as a potential therapeutic target for osteoporosis.

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