scholarly journals VEGF Promotes Proliferation of Human Glioblastoma Multiforme Stem-Like Cells through VEGF Receptor 2

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Chengshi Xu ◽  
Xing Wu ◽  
Jianhong Zhu
Keyword(s):  
Glioblastoma Multiforme ◽  
Vegf Receptor ◽  
Dependent Manner ◽  
Vascular Endothelial ◽  
Tumor Initiating Cells ◽  
Atp Assay ◽  
Human Glioblastoma Multiforme ◽  
Human Gbm ◽  
Endothelial Growth Factor ◽  
Dose Dependent

Cancer stem-like cells, which have been described as tumor-initiating cells or tumor-propagating cells, play a crucial role in our fundamental understanding of glioblastoma multiforme (GBM) and its recurrence. GBM is a lethal cancer, characterized by florid vascularization and aberrantly elevated vascular endothelial growth factor (VEGF). VEGF promotes tumorigenesis and angiogenesis of human GBM stem-like cells (GBSCs). However, whether and how VEGF contributes to GBSCs proliferation remain largely uncertain. In this study, human GBSCs were isolated from surgical specimens of glioblastoma and cultured in medium favored for stem cell growth. Neural Colony-Forming Cell Assay and ATP assay were performed to measure GBSC proliferation under normoxia (20% O2) and hypoxia (1% O2). Our observations demonstrate that exogenous VEGF stimulates GBSC proliferation in a dose-dependent manner via VEGF Receptor 2 (VEGFR2); while VEGF Receptor 1 (VEGFR1) has a negative feedback effect on VEGFR2 when cells were exposed to higher concentration of VEGF. These results suggest that suppressing VEGFR2-dependent GBSC proliferation is a potentially therapeutic strategy in GBM.

scholarly journals Mutual Regulation between PFKP and VEGF Promotes Glioblastoma Tumor Growth

2021 ◽  
Author(s):  
Jong-Ho Lee ◽  
Je Sun Lim ◽  
YuJie Shi ◽  
So Mi Jeon ◽  
Su Hwan Park ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Tumor Growth ◽  
Aerobic Glycolysis ◽  
Dependent Manner ◽  
Vascular Endothelial ◽  
Vegf Expression ◽  
Egfr Activation ◽  
Mutual Regulation ◽  
Human Gbm ◽  
Endothelial Growth Factor

Glioblastoma (GBM) is highly vascular malignant brain tumor that overexpresses vascular endothelial growth factor (VEGF) and phosphofructokinase 1 platelet isoform (PFKP), which catalyzes a rate-limiting reaction in glycolysis. However, it remains unknown whether PFKP and VEGF are reciprocally regulated during GBM tumor growth. Here, we show that PFKP promotes EGFR activation-induced VEGF expression in HIF-1α-dependent and -independent manners in GBM cells. Importantly, we demonstrate that EGFR-phosphorylated PFKP Y64 has critical roles in the AKT/SP1-mediated transcriptional expression of HIF-1α and in the AKT-mediated β-catenin S552 phosphorylation, to fully enhance VEGF transcription and subsequent blood vessel formation and brain tumor growth. The levels of PFKP Y64 phosphorylation in human GBM specimens positively correlate with HIF-1α expression, β-catenin S552 phosphorylation, and VEGF expression. Conversely, VEGF upregulates PFKP expression in a PFKP S386 phosphorylation-dependent manner, leading to increased PFK enzyme activity, aerobic glycolysis, and proliferation in GBM cells. These findings highlight a novel mechanism underlying the mutual regulation that occurs between PFKP and VEGF for promoting GBM tumor growth.

scholarly journals Regulation of the vascular endothelial growth factor (VEGF) receptor Flk-1/KDR by estradiol through VEGF in uterus

2006 ◽  
Vol 188 (1) ◽  
pp. 91-99 ◽  
Author(s):  
M A J Hervé ◽  
G Meduri ◽  
F G Petit ◽  
T S Domet ◽  
G Lazennec ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Endothelial Cells ◽  
Growth Factor ◽  
Receptor Expression ◽  
Maximal Response ◽  
Target Cells ◽  
Vegf Receptor ◽  
Dependent Manner ◽  
Vascular Endothelial ◽  
Endothelial Growth Factor

The induction of vascular endothelial growth factor (VEGF) expression by 17β-estradiol (E2) in many target cells, including epithelial cells, fibroblasts and smooth muscle cells, suggests a role for this hormone in the modulation of angiogenesis and vascular permeability. We have already described a cyclic increase in Flk-1/KDR-expressing capillaries in the human endometrium during the proliferative and mid-secretory phases, strongly suggestive of an E2 effect on Flk-1/KDR expression in the endometrial capillaries. However, it is unclear whether these processes are due to a direct effect of E2 on endothelial cells. Using immunohistochemistry, we report an increase in Flk-1/KDR expression in endometrial capillaries of ovariectomized mice treated with E2, or both E2 and progesterone. This process is mediated through estrogen receptor (ER) activation. In vitro experiments using quantitative RT-PCR analysis demonstrate that Flk-1/KDR expression was not regulated by E2 in human endothelial cells from the microcirculation (HMEC-1) or macrocirculation (HUVEC), even in endothelial cells overexpressing ERα or ERβ after ER-mediated adenovirus infection. In contrast, Flk-1/KDR expression was up-regulated by VEGF itself, in a time- and dose-dependent manner, with the maximal response at 10 ng/ml. Thus, we suggest that E2 up-regulates Flk-1/KDR expression in vivo in endothelial cells mainly through the modulation of VEGF by a paracrine mechanism. It is currently unknown whether or not the endothelial origin might account for differences in the E2-modulation of VEGF receptor expression, particularly in relation to the vascular bed of sex steroid-responsive tissues.

scholarly journals Vascular endothelial growth factor stimulates dephosphorylation of the catenins p120 and p100 in endothelial cells

2000 ◽  
Vol 346 (1) ◽  
pp. 209-216 ◽  
Author(s):  
Elaine Y. M. WONG ◽  
Louise MORGAN ◽  
Caroline SMALES ◽  
Paul LANG ◽  
Sharon E. GUBBY ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Endothelial Cells ◽  
Growth Factor ◽  
Molecular Mechanisms ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Extracellular Signal ◽  
Dose Dependent Decrease ◽  
Endothelial Growth Factor ◽  
Dose Dependent

Vascular endothelial growth factor (VEGF) is an endothelium-specific mitogen that induces angiogenesis and increases vascular permeability. These processes involve regulation of cell-cell adhesion, but molecular mechanisms have yet to be fully established. p120, also termed p120ctn, and its variant p100 are catenins which associate with cadherins and localize to adherens junctions. VEGF was reported to stimulate tyrosine phosphorylation of catenins in endothelial cells. In contrast, we have found that VEGF potently stimulated a rapid and dose-dependent decrease in serine/threonine phosphorylation of p120 and p100. VEGF acted via VEGF receptor 2 to achieve this effect which was independent of activation of the extracellular-signal-regulated kinase pathway. Histamine and activators of protein kinase C had a very similar effect to that of VEGF on phosphorylation of p120 and p100, suggesting that these diverse stimuli may converge on a common signalling element regulating p120/p100 serine/threonine phosphorylation. These data raise the possibility that the dephosphorylation of p120 and p100 triggered by VEGF may contribute to mechanisms regulating permeability and/or motility through modulation of cadherin adhesiveness.

scholarly journals Rap1 promotes VEGFR2 activation and angiogenesis by a mechanism involving integrin αvβ3

Blood ◽  
2011 ◽  
Vol 118 (7) ◽  
pp. 2015-2026 ◽  
Author(s):  
Sribalaji Lakshmikanthan ◽  
Magdalena Sobczak ◽  
Changzoon Chun ◽  
Angela Henschel ◽  
Jillian Dargatz ◽  
...  
Keyword(s):  
Integrin Αvβ3 ◽  
In Vivo Model ◽  
Vegf Receptor ◽  
Dependent Manner ◽  
Vascular Endothelial ◽  
Kinase Activation ◽  
Vegf Signaling ◽  
Endothelial Growth Factor

Abstract Vascular endothelial growth factor (VEGF) acting through VEGF receptor 2 (VEGFR2) on endothelial cells (ECs) is a key regulator of angiogenesis, a process essential for wound healing and tumor metastasis. Rap1a and Rap1b, 2 highly homologous small G proteins, are both required for angiogenesis in vivo and for normal EC responses to VEGF. Here we sought to determine the mechanism through which Rap1 promotes VEGF-mediated angiogenesis. Using lineage-restricted Rap1-knockout mice we show that Rap1-deficiency in endothelium leads to defective angiogenesis in vivo, in a dose-dependent manner. Using ECs obtained from Rap1-deficient mice we demonstrate that Rap1b promotes VEGF-VEGFR2 kinase activation and regulates integrin activation. Importantly, the Rap1b-dependent VEGF-VEGFR2 activation is in part mediated via integrin αvβ3. Furthermore, in an in vivo model of zebrafish angiogenesis, we demonstrate that Rap1b is essential for the sprouting of intersomitic vessels, a process known to be dependent on VEGF signaling. Using 2 distinct pharmacologic VEGFR2 inhibitors we show that Rap1b and VEGFR2 act additively to control angiogenesis in vivo. We conclude that Rap1b promotes VEGF-mediated angiogenesis by promoting VEGFR2 activation in ECs via integrin αvβ3. These results provide a novel insight into the role of Rap1 in VEGF signaling in ECs.

scholarly journals The cancer angiogenesis co-culture assay: In vitro quantification of the angiogenic potential of tumoroids

PLoS ONE ◽  
2021 ◽  
Vol 16 (7) ◽  
pp. e0253258
Author(s):  
Sarah Line Bring Truelsen ◽  
Nabi Mousavi ◽  
Haoche Wei ◽  
Lucy Harvey ◽  
Rikke Stausholm ◽  
...  
Keyword(s):  
Predictive Biomarkers ◽  
Tube Formation ◽  
Angiogenic Factor ◽  
Dependent Manner ◽  
Vascular Endothelial ◽  
Colorectal Tumour ◽  
Angiogenic Potential ◽  
Endothelial Growth Factor ◽  
Dose Dependent

The treatment response to anti-angiogenic agents varies among cancer patients and predictive biomarkers are needed to identify patients with resistant cancer or guide the choice of anti-angiogenic treatment. We present “the Cancer Angiogenesis Co-Culture (CACC) assay”, an in vitro Functional Precision Medicine assay which enables the study of tumouroid induced angiogenesis. This assay can quantify the ability of a patient-derived tumouroid to induce vascularization by measuring the induction of tube formation in a co-culture of vascular cells and tumoroids established from the primary colorectal tumour or a metastasis. Furthermore, the assay can quantify the sensitivity of patient-derived tumoroids to anti-angiogenic therapies. We observed that tube formation increased in a dose-dependent manner upon treatment with the pro-angiogenic factor vascular endothelial growth factor A (VEGF-A). When investigating the angiogenic potential of tumoroids from 12 patients we found that 9 tumoroid cultures induced a significant increase in tube formation compared to controls without tumoroids. In these 9 angiogenic tumoroid cultures the tube formation could be abolished by treatment with one or more of the investigated anti-angiogenic agents. The 3 non-angiogenic tumoroid cultures secreted VEGF-A but we observed no correlation between the amount of tube formation and tumoroid-secreted VEGF-A. Our data suggests that the CACC assay recapitulates the complexity of tumour angiogenesis, and when clinically verified, could prove a valuable tool to quantify sensitivity towards different anti-angiogenic agents.

Different Kinetics and Function of Vascular Endothelial Growth Factor Recepotor-1 and −2 during Hemangioblast Development from Primate Embryonic Stem Cells.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3920-3920
Author(s):  
Katsutsugu Umeda ◽  
Toshio Heike ◽  
Gen Shinoda ◽  
Akira Niwa ◽  
Masato Arai ◽  
...  
Keyword(s):  
Es Cells ◽  
Embryonic Stem ◽  
Cell Development ◽  
Dependent Manner ◽  
Vascular Endothelial ◽  
Blocking Antibody ◽  
Cd34 Cells ◽  
Low Levels ◽  
Endothelial Growth Factor ◽  
Dose Dependent

Abstract The close developmental association between hematopoietic and endothelial cells suggests that both lineage cells share a common precursor, the hemangioblast. The vascular endothelial growth factor (VEGF)-A system has been proven to have roles in the embryonic development of hemangioblast in mouse by the use of embryos or embryonic stem (ES) cells deprived of the genes encoding its ligand or receptors (VEGFR-1 and VEGFR-2). On the other hand, there have been only a few reports on the hemangioblast development during primate (human and monkey) embryogenesis. We have previously demonstrated that the hemangioblast is highly enriched in the VEGFR-2high CD34+ cell fraction, differentiated from cynomolgus monkey ES cells by 6-day coculture with OP9 stromal cells. In the current study, we examined whether the VEGF-A system was involved in the development of hemangioblast induced from primate ES cells by using the coculture system. VEGFR-1 and −2 were expressed by undifferentiated monkey ES cells at low levels. The VEGFR-2low cells gradually decreased while VEGFR-2high cells could be detected on day 6. On the other hand, VEGFR-1 was constantly expressed at low levels on day 6 and thereafter. Exogenous VEGF-A165, the action of which is mediated VEGFR-1 and VEGFR-2, increased the proportion of VEGFR-2high CD34+ cells in a dose-dependent manner. Addition of VEGF-E (VEGFR-2-specific agonist) and VEGFR-1 blocking antibody resulted in the increase of VEGFR-2high CD34+ cells in a dose-dependent manner, while VEGFR-2 blocking antibody suppressed their development. Thus, VEGF-A/VEGFR-2 interaction promoted the development of hemangioblast, while VEGF-A/VEGFR-1 interaction acted as a negative regulator. We then examined when VEGF-related signals work on VEGFR-2high cell development by changing factors on day 4. The proportion of VEGFR-2high CD34+ cells with the last 2-day VEGF-A165 and -E treatment were almost equivalent to that with continuous exposure to the VEGF. On the contrary, initial 4-day VEGF-A165 and -E treatment did not any stimulatory effects on VEGFR-2high CD34+ cell development. Our previous results show that during differentiation, Brachyury (early mesodermal marker) is first expressed on day 4, followed by the up-regulation of genes, such as SCL, LMO2, and MYB, representing hematopoietic and/or endothelial potentials on day 6. Collectively, VEGFR-2-mediated signals might contribute to the commitment and/or expansion of the hemangioblast rather than their development. This coculture system provides an opportunity to better understand the regulative mechanisms on early hematopoietic and endothelial cell development, which remains unresolved by experiments using human embryos.

scholarly journals Suppression of Development of Ankylosing Spondylitis Through Soluble Flt-1

2015 ◽  
Vol 37 (6) ◽  
pp. 2135-2142 ◽  
Author(s):  
Zhongxiang Yu ◽  
Yuting Zhang ◽  
Ningyang Gao ◽  
Kuang Yong
Keyword(s):  
Endothelial Cells ◽  
Ankylosing Spondylitis ◽  
Vegf Receptor ◽  
Dependent Manner ◽  
Vascular Endothelial ◽  
Treatment Results ◽  
Vegf Signaling ◽  
Before And After ◽  
Endothelial Growth Factor ◽  
Pro Inflammatory Cytokines

Background/Aims: Circulating monocytes/macrophages are origins of osteoclasts that mediate the development of ankylosing spondylitis (AS). Moreover, infiltrated macrophages facilitate the AS progression through production and secretion of pro-inflammatory cytokines. Thus, suppression of the recruitment of circulating monocytes/macrophages may be an effective AS treatment, which is, however, not available so far in clinic. Soluble fms-like tyrosine kinase-1 (sFlt-1) is a decoy receptor for vascular endothelial growth factor (VEGF) to compete with VEGF receptor (VEGFR2) for VEGF binding in endothelial cells, while its application in treating AS and effects on the recruitment of circulating monocytes/macrophages has not been reported before. Methods: We used a proteoglycan-induced arthritis (PGIA) mouse model for human AS. We injected sFlt-1 into the articular cavity and evaluated its effects on PGIA by incidence of arthritis, and clinical and pathological arthritis severity. We isolated and analyzed macrophages and endothelial cells in the articular cavity before and after treatment. Results: Injection of sFlt-1 significantly decreased the incidence and severity of PGIA in mice, and significantly reduced the number of infiltrated macrophages, possibly through reduction of vessel permeability, in a VEGFR2-dependent manner. Conclusion: Our data suggest that sFlt-1 may have a therapeutic effect on AS, resulting from suppression of VEGF signaling-mediated recruitment of circulating monocytes/macrophages.

scholarly journals Leishmania Infection Induces Macrophage Vascular Endothelial Growth Factor A Production in an ARNT/HIF-Dependent Manner

2019 ◽  
Vol 87 (11) ◽  
Author(s):  
Tiffany Weinkopff ◽  
Hayden Roys ◽  
Anne Bowlin ◽  
Phillip Scott
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Leishmania Major ◽  
Leishmania Infection ◽  
Vegf Receptor ◽  
Dependent Manner ◽  
Vascular Endothelial ◽  
Cell Type ◽  
Content Type ◽  
Endothelial Growth Factor

ABSTRACT Cutaneous leishmaniasis is characterized by vascular remodeling. Following infection with Leishmania parasites, the vascular endothelial growth factor A (VEGF-A)/VEGF receptor 2 (VEGFR-2) signaling pathway mediates lymphangiogenesis, which is critical for lesion resolution. Therefore, we investigated the cellular and molecular mediators involved in VEGF-A/VEGFR-2 signaling using a murine model of infection. We found that macrophages are the predominant cell type expressing VEGF-A during Leishmania major infection. Given that Leishmania parasites activate hypoxia-inducible factor 1α (HIF-1α) and this transcription factor can drive VEGF-A expression, we analyzed the expression of HIF-1α during infection. We showed that macrophages were also the major cell type expressing HIF-1α during infection and that infection-induced VEGF-A production is mediated by ARNT/HIF activation. Furthermore, mice deficient in myeloid ARNT/HIF signaling exhibited larger lesions without differences in parasite numbers. These data show that L. major infection induces macrophage VEGF-A production in an ARNT/HIF-dependent manner and suggest that ARNT/HIF signaling may limit inflammation by promoting VEGF-A production and, thus, lymphangiogenesis during infection.

scholarly journals Temporal Dynamics of VEGFA-Induced VEGFR2/FAK Co-Localization Depend on SHB

Cells ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 1645 ◽  
Author(s):  
Ilkka Pietilä ◽  
Djenolan Van Mourik ◽  
Andreas Tamelander ◽  
Vitezslav Kriz ◽  
Lena Claesson-Welsh ◽  
...  
Keyword(s):  
Temporal Dynamics ◽  
Focal Adhesions ◽  
Vegf Receptor ◽  
Dependent Manner ◽  
Vascular Endothelial ◽  
Src Homology 2 ◽  
Src Homology ◽  
Lung Endothelial Cells ◽  
Src Homology 2 Domain ◽  
Endothelial Growth Factor

Focal adhesion kinase (FAK) is essential for vascular endothelial growth factor-A (VEGFA)/VEGF receptor-2 (VEGFR2)-stimulated angiogenesis and vascular permeability. We have previously noted that presence of the Src homology-2 domain adapter protein B (SHB) is of relevance for VEGFA-stimulated angiogenesis in a FAK-dependent manner. The current study was conducted in order address the temporal dynamics of co-localization between these components in HEK293 and primary lung endothelial cells (EC) by total internal reflection fluorescence microscopy (TIRF). An early (<2.5 min) VEGFA-induced increase in VEGFR2 co-localization with SHB was dependent on tyrosine 1175 in VEGFR2. VEGFA also enhanced SHB co-localization with FAK. FAK co-localization with VEGFR2 was dependent on SHB since it was significantly lower in SHB deficient EC after VEGFA addition. Absence of SHB also resulted in a gradual decline of VEGFR2 co-localization with FAK under basal (prior to VEGFA addition) conditions. A similar basal response was observed with expression of the Y1175F-VEGFR2 mutant in wild type EC. The distribution of focal adhesions in SHB-deficient EC was altered with a primarily perinuclear location. These live cell data implicate SHB as a key component regulating FAK activity in response to VEGFA/VEGFR2.

scholarly journals Injectable nanoclay gels for angiogenesis

2019 ◽  
Author(s):  
Daniel J. Page ◽  
Claire E. Clarkin ◽  
Raj Mani ◽  
Najeed A. Khan ◽  
Jonathan I. Dawson ◽  
...  
Keyword(s):  
Growth Factor ◽  
Active Form ◽  
Fold Increase ◽  
Dependent Manner ◽  
Vascular Endothelial ◽  
Sustained Activity ◽  
A Site ◽  
Endothelial Growth Factor ◽  
Dose Dependent

AbstractThe retention and sustained activity of therapeutic proteins at delivery sites are goals of regenerative medicine. Vascular endothelial growth factor (VEGF) has significant potential in promoting the growth and regeneration of blood vessels but is intrinsically labile. This is exacerbated by the inflammatory microenvironments at sites requiring regeneration. For VEGF to be efficacious it may require a carrier that stabilises it, protects it from degradation and retains it at a site of interest. In this study we tested the hypothesis that injectable nanoclay gels composed of Laponite XLG can stabilise VEGF and retain it in active form for therapeutic delivery. To achieve this, VEGF was incorporated in Laponite gels and its activity tested at a range of concentrations using in vivo cell culture tubulogenesis assays and in vivo angiogenesis assays. We found that VEGF-Laponite gels enhanced tubulogenesis in a dose-dependent manner in vivo. When administered subcutaneously in vivo Laponite was retained at an injection site for up to a period of three weeks and promoted a 4-fold increase in blood vessel formation compared with alginate or vehicle controls as confirmed by CD31 staining. Notably, in contrast to alginate, Laponite gels did not release VEGF, indicating a strong interaction between the growth factor and the nanoclay, and suggesting that Laponite enhancement of VEGF efficacy is due to its retention at an implantation site over a prolonged period. Our approach provides a robust method for delivery of bioactive recombinant VEGF without the necessity for complex hydrogel or protein engineering.

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