scholarly journals AB0089 THE ANALYSIS FOR THE INHIBITION OF ANGIOGENESIS BY JAK INHIBITOR

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1344.2-1344
Author(s):  
M. Fujita ◽  
K. Fukuda ◽  
S. Hayashi ◽  
K. Kikuchi ◽  
Y. Takashima ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Tube Formation ◽  
Vascular Endothelial ◽  
Jak Inhibitors ◽  
Inhibitory Effects ◽  
Tube Formation Assay ◽  
Stat Signaling ◽  
Endothelial Growth Factor

Background:Many blood vessels are generated in the hyperplastic synovial tissue of patients with rheumatoid arthritis (RA), and lead to chronic tissue inflammation and joint destruction [1]. Janus kinase (JAK) family consisting of JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2) are chain receptors which phosphorylate signal transducers and activators of transcription (STAT) and mediate inflammatory diseases including RA [2]. Nowadays, several JAK inhibitors such as Tofacitinib (TOF), Baricitinib (BAR) and Peficitinib (PEF) have been developed and demonstrated to have the inhibitory effects on inflammatory arthritis [3-5]. However, there were few reports concerning their effects on angiogenesis in vitro.Objectives:The purpose of the present study is to investigate the influence of JAK inhibitors on angiogenesis of human umbilical vein endothelial cell (HUVEC) activated by vascular endothelial growth factor (VEGF).Methods:The cell line of HUVECs were used for this study. The activity of proliferation and tube formation were analyzed by counting assay and tube formation assay, respectively.In counting assay, HUVECs (5 × 104cells/ml) were seeded onto 96-well cell culture plate with 20 ng/ml VEGF including various doses (0.1µM, 1µM, 5µM) of TOF, BAR or PEF. After 48 hours incubation at 37°C in a humidified atmosphere containing 5% CO2, cell proliferation of each groups was assessed using cell counting kit. In tube formation assay, HUVECs (5 × 104cells/ml) were treated with 20ng/ml VEGF including various dose (0.1µM, 1µM, 5µM) of TOF, BAR or PEF for 00 hours, then seeded onto 48-well plate applied with Matrigel. After 24 hours incubation on Matrigel, the capillary-like tube formation of each well was photographed using phase contrast microscopy. Tube formation were quantitated by measurement of the length of branch.Results:HUVECs were activated in proliferation and tube formation by VEGF treatment. And, the proliferation and tube formation of HUVECs activated by VEGF were suppressed by All of TOF, BAR and PEF. In particular, TOF and PEF could suppress them highly.Conclusion:This study showed the inhibitory effect of JAK inhibitors on proliferation and tube formation of HUVECs activated by VEGF. In particular, the angiogenesis of HUVECs activated by VEGF was highly suppressed by TOF and PEF. VEGF is reported to regulate the angiogenesis through multi JAK-STAT signaling pathways [6]. The inhibitory effects on angiogenesis of TOF, BAR and PEF might depend on the differences in their affinity for JAKs. VEGF has been shown to a have a central involvement in the angiogenic process in RA [7]. JAK inhibitors might suppress the angiogenesis in RA synovial tissues by inhibiting VEGF signaling.References:[1]Scott DL, et al. Rheumatoid arthritis. Lancet. 2010.[2]Banerjee S, et al. JAK-STAT signaling as a target for inflammatory and autoimmune diseases: current and future prospects. Drugs. 2017.[3]William D, et al. JAK inhibitors in dermatology: the promise of a new drug class. Journal of the American Academy of Dermatology. 2017.[4]Dhillon S. Tofacitinib: A Review in Rheumatoid Arthritis. Drugs. 2017.[5]Markham A, et al. Peficitinib: First Global Approval. Drugs. 2019.[6]Zhang HY, et al. Three important components in the regeneration of the cavernous nerve: brain-derived neurotrophic factor, vascular endothelial growth factor and the JAK/STAT signaling pathway. Asian journal of andrology. 2011.[7]Paleolog EM. Angiogenesis in rheumatoid arthritis. Arthritis research. 2002.Acknowledgments:noneDisclosure of Interests:None declared

Alteration in angiogenic potential of granulosa-lutein cells and follicular fluid contributes to luteal defects in polycystic ovary syndrome

2020 ◽  
Author(s):  
Krutika Patil ◽  
Indira Hinduja ◽  
Srabani Mukherjee
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Endothelial Cell ◽  
Growth Factor ◽  
Polycystic Ovary ◽  
Tube Formation ◽  
Vascular Endothelial ◽  
Transcript Levels ◽  
Angiogenic Potential ◽  
Angiogenic Genes ◽  
Endothelial Growth Factor

Abstract STUDY QUESTION Is angiogenic potential of follicular fluid (FF) and granulosa-lutein cells (GLCs) altered in polycystic ovary syndrome (PCOS) and does it play a role in corpus luteum (CL) defect observed in them? SUMMARY ANSWER FF and GLCs of women with PCOS show reduced expression of pro-angiogenic factors compared to controls and exhibit a diminished capacity to induce angiogenesis. WHAT IS KNOWN ALREADY In women with PCOS, CL insufficiency and frequent miscarriage are reported, which may be due to defect in CL. The development of new blood vessels is essential to promote ovarian folliculogenesis and functional CL formation. The vasculature formation in CL which is important for its function is still unexplored in these women. STUDY DESIGN, SIZE, DURATION This case-control study was conducted in 30 healthy control women and 30 women with PCOS undergoing controlled ovarian hyperstimulation for IVF. The FF, GLCs and serum were collected from all participants during ovum pick up. PARTICIPANTS/MATERIALS, SETTING, METHODS The capacity of FF to induce angiogenesis was assessed by measuring levels of pro-angiogenic factors vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF2) and its tube formation and wound healing potential using human umbilical vein endothelial cells (HUVECs). We investigated the angiogenic potential and endothelial cell-like nature of GLCs using several approaches such as the expression of angiogenic genes by quantitative PCR, DiI-conjugated acetylated low-density lipoproteins (Dil-Ac-LDL) internalization assay, tube formation assay, expression of endothelial cell markers by immunofluorescence analysis. In addition, correlation of transcript levels of angiogenic genes with oocyte parameters was studied. MAIN RESULTS AND THE ROLE OF CHANCE FF and serum levels of VEGF and FGF2 were significantly higher and lower, respectively, in PCOS compared to controls. The tube formation and wound healing capacity of HUVECs was found to be reduced when measured after supplementation with FF of women with PCOS compared to controls. This suggests a decreased angiogenic capacity of FF in women with PCOS. Tube formation (P = 0.003) and Dil-Ac-LDL internalization (P = 0.03) ability of GLCs were significantly reduced in women with PCOS compared to controls. Protein expression levels of endothelial markers, vascular endothelial growth factor A (VEGFA) (P = 0.004), vascular endothelial growth factor receptor 2 (VEGFR2) (P = 0.011), TEK Receptor Tyrosine Kinase (Tie-2) (P = 0.026), fibroblast growth factor receptor 1 (FGFR1) (P = 0.026) and CD31 (P = 0.035) and transcript levels of angiogenic genes VEGFA (P = 0.042), hypoxia inducing factor 1A (HIF1A) (P = 0.025), FGF2 (P = 0.038), angiopoietin 1 (ANGPT1) (P = 0.028), heparin sulfate proteoglycan 2 (HSPG2) (P = 0.016), ADAM metallopeptidase with thrombospondin type1 motif, 1 (ADAMTS1) (P = 0.027) and fibronectin 1 (FN1) (P = 0.016) were found to be low in GLCs of PCOS compared to controls. Thus, the findings of this study indicate that endothelial cell-like characteristics of GLCs were significantly decreased in PCOS. Furthermore, transcript levels of VEGFA (r = 0.46, P = 0.009), ADAMTS1 (r = 0.55, P = 0.001), FGF2 (r = 0.42, P = 0.022) and ANGPT2 (r = 0.47, P = 0.008) showed a positive correlation with oocyte fertilization rate. LIMITATIONS, REASONS FOR CAUTION The vasculature formation in CL is not possible to study in women, but we explored the angiogenic characteristics of FF and GLC obtained from women with PCOS to speculate any vascularization defect of CL in these women. The FF and GLCs were obtained from the stimulated cycle during oocyte retrieval, which may not exactly mimic the in-vivo condition. The small sample size is another limitation of this study. Larger sample size and support by color Doppler studies on CL blood flow would help to strengthen our findings. WIDER IMPLICATIONS OF THE FINDINGS Our findings suggest that the altered angiogenic potential of FF and GLCs may affect vasculature development required for CL formation and function in PCOS. These findings pave the way to devise therapeutic strategies to support angiogenesis process in follicle of women with PCOS, which may improve CL insufficiency, progesterone levels and prevent frequent miscarriages in these women. Furthermore, our study also hypothesizes that the vascularization around the ovarian follicles is also compromised which may lead to the growth arrest of the follicles in PCOS, however, this needs thorough investigations. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by Grant BT/PR16524/MED/97/346/2016 from the Department of Biotechnology, Government of India. The authors have no conflicts of interest to disclose. TRIAL REGISTRATION NUMBER N/A

scholarly journals Pro-Angiogenic Effects of Resveratrol in Brain Endothelial Cells: Nitric Oxide-Mediated Regulation of Vascular Endothelial Growth Factor and Metalloproteinases

2012 ◽  
Vol 32 (5) ◽  
pp. 884-895 ◽  
Author(s):  
Fabricio Simão ◽  
Aline S Pagnussat ◽  
Ji Hae Seo ◽  
Deepti Navaratna ◽  
Wendy Leung ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Vascular Endothelial Growth Factor ◽  
Endothelial Cells ◽  
Growth Factor ◽  
Signaling Pathways ◽  
Tube Formation ◽  
Mitogen Activated Protein Kinase ◽  
Vascular Endothelial ◽  
Cerebral Endothelial Cells ◽  
Endothelial Growth Factor

Resveratrol may be a powerful way of protecting the brain against a wide variety of stress and injury. Recently, it has been proposed that resveratrol not only reduces brain injury but also promotes recovery after stroke. But the underlying mechanisms are unclear. Here, we tested the hypothesis that resveratrol promotes angiogenesis in cerebral endothelial cells and dissected the signaling pathways involved. Treatment of cerebral endothelial cells with resveratrol promoted proliferation, migration, and tube formation in Matrigel assays. Consistent with these pro-angiogenic responses, resveratrol altered endothelial morphology resulting in cytoskeletal rearrangements of β-catenin and VE-cadherin. These effects of resveratrol were accompanied by activation of phosphoinositide 3 kinase (PI3-K)/Akt and Mitogen-Activated Protein Kinase (MAPK)/ERK signaling pathways that led to endothelial nitric oxide synthase upregulation and increased nitric oxide (NO) levels. Subsequently, elevated NO signaling increased vascular endothelial growth factor and matrix metalloproteinase levels. Sequential blockade of these signaling steps prevented resveratrol-induced angiogenesis in cerebral endothelial cells. These findings provide a mechanistic basis for the potential use of resveratrol as a candidate therapy to promote angiogenesis and neurovascular recovery after stroke.

Elevated levels of serum vascular endothelial growth factor in patients with rheumatoid arthritis

2009 ◽  
Vol 42 (4-5) ◽  
pp. 343
Author(s):  
Pinar Tonbaklar Bilgi ◽  
Esra Cetin ◽  
Levent Ozgonenel ◽  
Aram Aslan ◽  
Hale Aral ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Vascular Endothelial ◽  
Endothelial Growth Factor

Matrix stiffness primes lymphatic tube formation directed by vascular endothelial growth factor‐C

2021 ◽  
Vol 35 (5) ◽  
Author(s):  
Laura Alderfer ◽  
Elizabeth Russo ◽  
Adriana Archilla ◽  
Brian Coe ◽  
Donny Hanjaya‐Putra
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Tube Formation ◽  
Vascular Endothelial ◽  
Matrix Stiffness ◽  
Factor C ◽  
Endothelial Growth Factor

Glipizide Combined with ANP Suppresses Breast Cancer Growth and Metastasis by Inhibiting Angiogenesis through VEGF/VEGFR2 Signaling

2021 ◽  
Vol 21 ◽  
Author(s):  
Guanquan Mao ◽  
Shuting Zheng ◽  
Jinlian Li ◽  
Xiaohua Liu ◽  
Qin Zhou ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Natriuretic Peptide ◽  
Umbilical Vein ◽  
Tube Formation ◽  
Cancer Growth ◽  
Vascular Endothelial ◽  
Breast Cancer Growth ◽  
Endothelial Growth Factor

Background: Breast cancer is one of the most common cancers worldwide among women, and angiogenesis has an important effect on its growth and metastasis. Glipizide, which is a widely used drug for type 2 diabetes mellitus, has been reported to inhibit tumor growth and metastasis by upregulating the expression of natriuretic peptide receptor A (NPRA). Atrial natriuretic peptide (ANP), the receptor of NPRA, plays an important role in angiogenesis. The purpose of this study was to explore the effect of glipizide combined with ANP on breast cancer growth and metastasis. Methods: To investigate the effect of glipizide combined with ANP on breast cancer, glipizide, ANP or glipizide combined with ANP was intraperitoneally injected into MMTV-PyMT mice. To explore whether the anticancer efficacy of glipizide combined with ANP was correlated with angiogenesis, a tube formation assay was performed. Results: Glipizide combined with ANP was found to inhibit breast cancer growth and metastasis in MMTV-PyMT mice, which spontaneously develop breast cancer. Furthermore, the inhibitory effect of ANP combined with glipizide was better than that of glipizide alone. ANP combined with glipizide significantly inhibited tube formation of human umbilical vein endothelial cells (HUVECs) by suppressing vascular endothelial growth factor (VEGF)/VEGFR2 (vascular endothelial growth factor receptor 2) signaling. Conclusions: These results demonstrate that glipizide combined with ANP has a greater potential than glipizide alone to be repurposed as effective agents for the treatment of breast cancer by targeting tumor-induced angiogenesis.

scholarly journals Polymorphism in the regulatory regions –С2578A and +C936T of the vascular endothelial growth factor (VEGF-A) gene in Russian women with rheumatoid arthritis

2017 ◽  
Vol 89 (5) ◽  
pp. 60-64 ◽  
Author(s):  
A V Shevchenko ◽  
V F Prokofyev ◽  
M A Korolev ◽  
N E Banshchikova ◽  
V I Konenkov
Keyword(s):  
Rheumatoid Arthritis ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Polymorphism Analysis ◽  
Vascular Endothelial ◽  
Vegf Gene ◽  
Regulatory Regions ◽  
Female Patients ◽  
Healthy Women ◽  
Endothelial Growth Factor

Aim. To analyze polymorphism in the regulatory regions of the vascular endothelial growth factor (VEGF) gene in female patients with rheumatoid arthritis (RA). Subjects and methods. The investigation enrolled 257 female patients with RA. A control group consisted of 297 women without chronic diseases. The investigators examined the single-nucleotide polymorphism of VEGF-А2578С in the promoter region (rs699947) and that of VEGF+С936Т 3 in the retranslated region (rs3025039) of the gene. Genotyping was performed by restriction fragment length polymorphism analysis. Results. There was an increase in the frequency of VEGF+936 CT and a reduction in that of the VEGF+936СС genotypes in the seronegative patients as compared to the healthy women. The VEGF+936СС genotype frequency was higher in the patients with seropositive RA than in the subgroup of seronegative patients. The frequency of the VEGF-2578СС genotype was increased in the patients with RA and rheumatoid nodules, as compared to the healthy women. Conclusion. The data presented suggest that the presence of certain VEGF gene variants located in the regulatory regions may reflect the nature of immunopathological mechanisms in RA.

Knockdown of Nrf2 inhibits angiogenesis by downregulating VEGF expression through PI3K/Akt signaling pathway in cerebral microvascular endothelial cells under hypoxic conditions

2018 ◽  
Vol 96 (4) ◽  
pp. 475-482 ◽  
Author(s):  
Yujing Huang ◽  
Ying Mao ◽  
Huiying Li ◽  
Guangxun Shen ◽  
Guangxian Nan
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Ischemic Stroke ◽  
Growth Factor ◽  
Signaling Pathway ◽  
Akt Signaling ◽  
Tube Formation ◽  
Vascular Endothelial ◽  
Akt Signaling Pathway ◽  
Microvascular Endothelial ◽  
Endothelial Growth Factor

Ischemic stroke is a major cerebrovascular disease resulting from a transient or permanent local reduction of cerebral blood flow. Angiogenesis plays an important role in cerebral microvascular repair after ischemic stroke. This study aimed at investigating the effect of NF-E2-related factor 2 (Nrf2) on the angiogenesis of mouse cerebral microvascular endothelial bEnd.3 cells in a hypoxic environment. We found that Nrf2 expression was temporarily increased in hypoxia-induced bEnd.3 cells. Knockdown of Nrf2 inhibited the proliferation, migration, as well as tube formation in hypoxia-induced bEnd.3 cells. Meanwhile, vascular endothelial growth factor and PI3K/Akt signaling pathways were identified to be regulated by Nrf2 in hypoxia-induced bEnd.3 cells. It was found that silencing of Nrf2 downregulated the expression levels of NAD(P)H:quinine oxidoreductase-1, vascular endothelial growth factor, p-Akt, and heme oxygenase-1 in hypoxia-induced bEnd.3 cells. Data suggested that hypoxia induced the transient increase of Nrf2, which plays a key role in the angiogenesis of cerebral microangiogenesis, and that Nrf2 regulates the proliferation, migration, as well as tube formation likely through PI3K/Akt signaling pathway in hypoxia-induced bEnd.3 cells. Our study provides proof of concept for the modulation of Nrf2, so as to tilt the balance toward angiogenesis, representing a therapeutic strategy for hypoxia or ischemia disorders such as stroke.

scholarly journals Defining an Upstream VEGF (Vascular Endothelial Growth Factor) Priming Signature for Downstream Factor-Induced Endothelial Cell-Pericyte Tube Network Coassembly

2020 ◽  
Vol 40 (12) ◽  
pp. 2891-2909
Author(s):  
Stephanie L.K. Bowers ◽  
Scott S. Kemp ◽  
Kalia N. Aguera ◽  
Gretchen M. Koller ◽  
Joshua C. Forgy ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Endothelial Cell ◽  
Growth Factor ◽  
Protein Kinase ◽  
Rho Kinase ◽  
Tube Formation ◽  
Vascular Endothelial ◽  
Heparin Binding ◽  
Il Interleukin ◽  
Endothelial Growth Factor

Objective: In this work, we have sought to define growth factor requirements and the signaling basis for different stages of human vascular morphogenesis and maturation. Approach and Results: Using a serum-free model of endothelial cell (EC) tube morphogenesis in 3-dimensional collagen matrices that depends on a 5 growth factor combination, SCF (stem cell factor), IL (interleukin)-3, SDF (stromal-derived factor)-1α, FGF (fibroblast growth factor)-2, and insulin (factors), we demonstrate that VEGF (vascular endothelial growth factor) pretreatment of ECs for 8 hours (ie, VEGF priming) leads to marked increases in the EC response to the factors which includes; EC tip cells, EC tubulogenesis, pericyte recruitment and proliferation, and basement membrane deposition. VEGF priming requires VEGFR2, and the effect of VEGFR2 is selective to the priming response and does not affect factor-dependent tubulogenesis in the absence of priming. Key molecule and signaling requirements for VEGF priming include RhoA, Rock1 (Rho-kinase), PKCα (protein kinase C α), and PKD2 (protein kinase D2). siRNA suppression or pharmacological blockade of these molecules and signaling pathways interfere with the ability of VEGF to act as an upstream primer of downstream factor-dependent EC tube formation as well as pericyte recruitment. VEGF priming was also associated with the formation of actin stress fibers, activation of focal adhesion components, upregulation of the EC factor receptors, c-Kit, IL-3Rα, and CXCR4 (C-X-C chemokine receptor type 4), and upregulation of EC-derived PDGF (platelet-derived growth factor)-BB, PDGF-DD, and HB-EGF (heparin-binding epidermal growth factor) which collectively affect pericyte recruitment and proliferation. Conclusions: Overall, this study defines a signaling signature for a separable upstream VEGF priming step, which can activate ECs to respond to downstream factors that are necessary to form branching tube networks with associated mural cells.

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