scholarly journals Endothelial specific YY1 deletion restricts tumor angiogenesis and tumor growth

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Huan Liu ◽  
Yikai Qiu ◽  
Xiuying Pei ◽  
Ramamurthy Chitteti ◽  
Rebbeca Steiner ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Tumor Growth ◽  
Tumor Angiogenesis ◽  
Molecular Mechanisms ◽  
Vascular Endothelial Cells ◽  
Umbilical Vein ◽  
Vital Role ◽  
Vascular Endothelial

AbstractAngiogenesis is a physiological process for the formation of new blood vessels from the pre-existing vessels and it has a vital role in the survival and growth of neoplasms. During tumor angiogenesis, the activation of the gene transcriptions in vascular endothelial cells (ECs) plays an essential role in the promotion of EC proliferation, migration, and vascular network development. However, the molecular mechanisms underlying transcriptional regulation of EC and tumor angiogenesis remains to be fully elucidated. Here we report that the transcription factor Yin Yang 1 (YY1) in ECs is critically involved in tumor angiogenesis. First, we utilized a tamoxifen-inducible EC-specific YY1 deficient mouse model and showed that YY1 deletion in ECs inhibited the tumor growth and tumor angiogenesis. Using the in vivo matrigel plug assay, we then found that EC-specific YY1 ablation inhibited growth factor-induced angiogenesis. Furthermore, vascular endothelial growth factor (VEGF)-induced EC migration was diminished in YY1-depleted human umbilical vein endothelial cells (HUVECs). Finally, a rescue experiment revealed that YY1-regulated BMP6 expression in ECs was involved in EC migration. Collectively, our results demonstrate that endothelial YY1 has a crucial role in tumor angiogenesis and suggest that targeting endothelial YY1 could be a potential therapeutic strategy for cancer treatment.

scholarly journals Synthesis and physiological activity of heterodimers comprising different splice forms of vascular endothelial growth factor and placenta growth factor

1996 ◽  
Vol 316 (3) ◽  
pp. 703-707 ◽  
Author(s):  
Ralf BIRKENHÄGER ◽  
Bernard SCHNEPPE ◽  
Wolfgang RÖCKL ◽  
Jörg WILTING ◽  
Herbert A. WEICH ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Vascular Endothelial Cells ◽  
Physiological Activity ◽  
Expression System ◽  
Vascular Endothelial ◽  
Placenta Growth Factor ◽  
Splice Forms

Vascular endothilial growth factor (VEGF) and placenta growth factor (PIGF) are members of a dimeric-growth-factor family with angiogenic properties. VEGF is a highly potent and specific mitogen for endothelial cells, playing a vital role in angiogenesis in vivo. The role of PIGF is less clear. We expressed the monomeric splice forms VEGF-165, VEGF-121, PIGF-1 and PlGF-2 as unfused genes in Escherichia coli using the pCYTEXP expression system. In vitro dimerization experiments revealed that both homo- and hetero-dimers can be formed from these monomeric proteins. The dimers were tested for their ability to promote capillary growth in vivo and stimulate DNA synthesis in cultured human vascular endothelial cells. Heterodimers comprising different VEGF splice forms, or combinations of VEGF/PlGF splice forms, showed mitogenic activity. The results demonstrate that four different heterodimeric growth factors are likely to have as yet uncharacterized functions in vivo.

scholarly journals DEPTOR Deficiency-Mediated mTORc1 Hyperactivation in Vascular Endothelial Cells Promotes Angiogenesis

2018 ◽  
Vol 46 (2) ◽  
pp. 520-531 ◽  
Author(s):  
Yan Ding ◽  
Lanlan Shan ◽  
Wenqing Nai ◽  
Xiaojun Lin ◽  
Ling Zhou ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Gene Knockout ◽  
Umbilical Vein ◽  
Vascular Endothelial Cell ◽  
Tube Formation ◽  
Vascular Endothelial

Background/Aims: The mechanistic target of rapamycin (mTOR) signaling pathway is essential for angiogenesis and embryonic development. DEP domain-containing mTOR-interacting protein (DEPTOR) is an mTOR binding protein that functions to inhibit the mTOR pathway In vitro experiments suggest that DEPTOR is crucial for vascular endothelial cell (EC) activation and angiogenic responses. However, knowledge of the effects of DEPTOR on angiogenesis in vivo is limited. This study aimed to determine the role of DEPTOR in tissue angiogenesis and to elucidate the molecular mechanisms. Methods: Cre/loxP conditional gene knockout strategy was used to delete the Deptor gene in mouse vascular ECs. The expression or distribution of cluster of differentiation 31 (CD31), vascular endothelial growth factor (VEGF) and hypoxia inducible factor-1 alpha (HIF-1α) were detected by immunohistochemical staining or western blot. Tube formation assay was used to measure angiogenesis in vitro. Results: Deptor knockdown led to increased expression of CD31, VEGF and HIF-1α in heart, liver, kidney and aorta. After treatment with rapamycin, their expression was significantly down regulated. In vitro, human umbilical vein endothelial cells (HUVECs) were transfected with DEPTOR-specific small interfering RNA (siRNA), which resulted in a significant increase in endothelial tube formation and migration rates. In contrast, DEPTOR overexpression markedly reduced the expression of CD31, VEGF and HIF-1α. Conclusions: Our findings demonstrated that deletion of the Deptor gene in vascular ECs resulted in upregulated expression of CD31 and HIF-1α, and further stimulated the expression of VEGF which promoted angiogenesis, indicating that disruption of normal angiogenic pathways may occur through hyperactivation of the mTORC1/HIF-1α/VEGF signaling pathway.

Vascular endothelial growth factor–stimulated endothelial cells promote adhesion and activation of platelets

Blood ◽  
2000 ◽  
Vol 96 (13) ◽  
pp. 4216-4221 ◽  
Author(s):  
Henk M. W. Verheul ◽  
Anita S. Jorna ◽  
Klaas Hoekman ◽  
Henk J. Broxterman ◽  
Martijn F. B. G. Gebbink ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Endothelial Cells ◽  
Growth Factor ◽  
Platelet Adhesion ◽  
Umbilical Vein ◽  
Vascular Endothelial ◽  
High Affinity Binding Site ◽  
Umbilical Vein Endothelial Cells ◽  
Endothelial Growth Factor

Abstract Coagulation abnormalities, including an increased platelet turnover, are frequently found in patients with cancer. Because platelets secrete angiogenic factors on activation, this study tested the hypothesis that platelets contribute to angiogenesis. Stimulation with vascular endothelial growth factor (VEGF, 25 ng/mL) of human umbilical vein endothelial cells (HUVECs) promoted adhesion of nonactivated platelets 2.5-fold. In contrast, stimulation of HUVECs with basic fibroblast growth factor (bFGF) did not promote platelet adhesion. By blocking tissue factor (TF) activity, platelet adhesion was prevented and antibodies against fibrin(ogen) and the platelet-specific integrin, αIIbβ3, inhibited platelet adhesion for 70% to 90%. These results indicate that VEGF-induced platelet adhesion to endothelial cells is dependent on activation of TF. The involvement of fibrin(ogen) and the αIIbβ3 integrin, which exposes a high-affinity binding site for fibrin(ogen) on platelet activation, indicates that these adhering platelets are activated. This was supported by the finding that the activity of thrombin, a product of TF-activated coagulation and a potent platelet activator, was required for platelet adhesion. Finally, platelets at physiologic concentrations stimulated proliferation of HUVECs, indicative of proangiogenic activity in vivo. These results support the hypothesis that platelets contribute to tumor-induced angiogenesis. In addition, they may explain the clinical observation of an increased platelet turnover in cancer patients. Platelets may also play an important role in other angiogenesis-dependent diseases in which VEGF is involved, such as diabetes and autoimmune diseases.

Epidermal Growth Factor Stimulates Prostacyclin Production by Cultured Human Vascular Endothelial Cells

1988 ◽  
Vol 59 (02) ◽  
pp. 248-250 ◽  
Author(s):  
Ari Ristimäki ◽  
Olavi Ylikorkala ◽  
Jaakko Perheentupa ◽  
Lasse Viinikka
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Vascular Endothelial Cells ◽  
Umbilical Vein ◽  
Fold Increase ◽  
Protein Synthesis Inhibitor ◽  
Vascular Endothelial ◽  
Synthesis Inhibitor ◽  
Epidermal Growth

SummaryEpidermal growth factor (EGF) stimulated prostacyclin (PGI2) production by cultured human umbilical vein endothelial cells, as measured by radioimmunoassay of its stable metabolite 6-keto- prostaglandin Flα. This effect of EGF was dose-dependent, the lowest stimulatory concentration of EGF was 1.0 ng/ml and 100 ng/ml caused a 2.7 ± 0.3 (mean ± SEM) fold increase in the PGI2 synthesis. The stimulation appeared at 3-6 h of incubation and lasted at least 24 h. It was suppressed by EGF antibodies and blocked by protein synthesis inhibitor cycloheximide. Cells preincubated 12 h with EGF released also higher amounts of PGI2when incubated with thrombin for 5 min. It is concluded that EGF liberated from platelets during aggregation may prevent local thrombogenesis and atherogenesis by stimulating the release of the antiaggregatory, vasodilatory PGI2 from vascular endothelial cells.

scholarly journals Exosome-encapsulated miR-505 from ox-LDL-treated vascular endothelial cells aggravates atherosclerosis by inducing NET formation

2019 ◽  
Vol 51 (12) ◽  
pp. 1233-1241 ◽  
Author(s):  
Li Chen ◽  
Liqun Hu ◽  
Qing Li ◽  
Jian Ma ◽  
Hongqi Li
Keyword(s):  
Endothelial Cells ◽  
Peripheral Blood ◽  
Vascular Endothelial Cells ◽  
Umbilical Vein ◽  
Density Lipoprotein ◽  
Luciferase Reporter ◽  
Vascular Endothelial ◽  
Healthy Donors ◽  
Net Release

Abstract Neutrophil extracellular traps (NETs) play an important role in the pathological process of atherosclerosis (AS). This study aims to evaluate whether exosomes from oxidized low-density lipoprotein (ox-LDL)-treated vascular endothelial cells (VECs) aggravate AS by inducing NET formation. Exosomes from the peripheral blood of healthy donors and AS patients (namely NC-EXO and AS-EXO, respectively) and exosomes from human umbilical vein endothelial cells (HUVECs) treated without or with ox-LDL (namely normal EXO and ox-LDL-EXO, respectively) were isolated, identified, and co-cultured with neutrophils from peripheral blood of healthy donors. NET formation was evaluated by immunofluorescence staining and determining the content of cell-free DNA and myeloperoxidase-DNA complex. Dual-luciferase reporter assay, chromatin immunoprecipitation assay, quantitative reverse transcription polymerase chain reaction, and western blot analysis were performed to explore the underlying mechanisms. We found that AS-EXO and ox-LDL-EXO induced NET release from neutrophils. Mechanistically, ox-LDL treatment in HUVECs might activate the NF-κB pathway, which transcriptionally activates miR-505, and then the exosome-encapsulated high miR-505 expression targeted and inhibited SIRT3 in neutrophils, thereby inducing reactive oxygen species (ROS) level increase and NET release by neutrophils. Further in vivo experiments showed that ox-LDL-EXO accelerated AS progression in AS mice. In summary, exosome-encapsulated miR-505 from ox-LDL-treated VECs aggravates AS by inducing NET formation.

scholarly journals Oncodevelopmental α-Fetoprotein Acts as a Selective Proangiogenic Factor on Endothelial Cell from the Fetomaternal Unit

2004 ◽  
Vol 89 (3) ◽  
pp. 1415-1422 ◽  
Author(s):  
Olin D. Liang ◽  
Thomas Korff ◽  
Jessica Eckhardt ◽  
Jasmin Rifaat ◽  
Nelli Baal ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Endothelial Cells ◽  
Growth Factor ◽  
Umbilical Vein ◽  
Chorioallantoic Membrane ◽  
Protein S ◽  
First Trimester ◽  
Vascular Endothelial ◽  
Endothelial Growth Factor

Abstract The molecular coordination between angiogenesis and vascular remodeling is a critical step for the development of a functional vasculature in the placenta and the uterus during pregnancy. The oncodevelopmental albumin homolog α-fetoprotein (AFP) is mainly synthesized in the developing fetus, and its expression has been found to be associated with highly vascularized tumors in the adult. In this study, we investigated the angiogenic activity of AFP and its possible role in the fetomaternal unit. Immunohistochemical studies revealed that the AFP-binding protein(s) is expressed in blood vessels of chorionic villi from placentae of the second and the third but not of the first trimester during pregnancy. At low concentrations, AFP directly stimulates or enhances, respectively, vascular endothelial growth factor-induced proliferation and sprout formation of endothelial cells isolated from the placenta and the uterus possibly by a MAPK-dependent pathway. Furthermore, AFP enhances blood vessel formation in a chick chorioallantoic membrane assay in vivo. Interestingly, AFP has no proliferative or migratory effects on endothelial cells isolated from the umbilical vein in the absence of vascular endothelial growth factor. These data indicate that AFP may act as a specific proangiogenic factor of endothelial cells within the fetomaternal unit during advanced stages in pregnancy.

scholarly journals The mechanism of all-trans retinoic acid in the regulation of apelin expression in vascular endothelial cells

2017 ◽  
Vol 37 (6) ◽  
Author(s):  
Hongyun Shi ◽  
Lanhui Yuan ◽  
Huibin Yang ◽  
Aimin Zang
Keyword(s):  
Endothelial Cells ◽  
Retinoic Acid ◽  
Vascular Endothelial Cells ◽  
Retinoic Acid Receptor ◽  
Umbilical Vein ◽  
Vascular Endothelial Cell ◽  
Vascular Endothelial ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

The apelin gene can promote vascular endothelial cell (VEC) proliferation, migration, and angiogenesis. However, the molecular mechanism for regulation of the apelin gene is still unknown. Real-time PCR and Western blotting analysis were employed to detect the effect of all-trans retinoic acid (ATRA) in up-regulating apelin expression in human umbilical vein endothelial cells (HUVECs). Furthermore, the in vivo study also indicated that ATRA could increase apelin expression in balloon-injured arteries of rats, which is consistent with the results from the cultured HUVECs. To ensure whether retinoic acid receptor (RAR) α (RARα) could be induced by ATRA in regulating apelin, the expression of RARα was tested with a siRNA method to knock down RARα or adenovirus vector infection to overexpress RARα. The results showed that ATRA could up-regulate apelin expression time- and dose- dependently in HUVECs. ATRA could induce a RARα increase; however, the expression of RARβ and RARγ were unchanged. The blocking of RARα signaling reduced the response of apelin to ATRA when HUVECs were treated with RARα antagonists (Ro 41-5253) or the use of siRNA against RARα (si-RARα) knockdown RARα expression before using ATRA. In addition, induction of RARα overexpression by infection with pAd-GFP-RARα further increased the induction of apelin by ATRA. These results suggested that ATRA up-regulated apelin expression by promoting RARα signaling.

scholarly journals Carbonic anhydrase 2 (CAII) supports tumor blood endothelial cell survival under lactic acidosis in the tumor microenvironment

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Dorcas A. Annan ◽  
Nako Maishi ◽  
Tomoyoshi Soga ◽  
Randa Dawood ◽  
Cong Li ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Endothelial Cells ◽  
Lactic Acid ◽  
Growth Factor ◽  
Carbonic Anhydrase ◽  
Lactic Acidosis ◽  
Tumor Angiogenesis ◽  
Vascular Endothelial ◽  
Endothelial Growth Factor

Abstract Background Tumor endothelial cells (TECs) perform tumor angiogenesis, which is essential for tumor growth and metastasis. Tumor cells produce large amounts of lactic acid from glycolysis; however, the mechanism underlying the survival of TECs to enable tumor angiogenesis under high lactic acid conditions in tumors remains poorly understood. Methodology The metabolomes of TECs and normal endothelial cells (NECs) were analyzed by capillary electrophoresis time-of-flight mass spectrometry. The expressions of pH regulators in TECs and NECs were determined by quantitative reverse transcription-PCR. Cell proliferation was measured by the MTS assay. Western blotting and ELISA were used to validate monocarboxylate transporter 1 and carbonic anhydrase 2 (CAII) protein expression within the cells, respectively. Human tumor xenograft models were used to access the effect of CA inhibition on tumor angiogenesis. Immunohistochemical staining was used to observe CAII expression, quantify tumor microvasculature, microvessel pericyte coverage, and hypoxia. Results The present study shows that, unlike NECs, TECs proliferate in lactic acidic. TECs showed an upregulated CAII expression both in vitro and in vivo. CAII knockdown decreased TEC survival under lactic acidosis and nutrient-replete conditions. Vascular endothelial growth factor A and vascular endothelial growth factor receptor signaling induced CAII expression in NECs. CAII inhibition with acetazolamide minimally reduced tumor angiogenesis in vivo. However, matured blood vessel number increased after acetazolamide treatment, similar to bevacizumab treatment. Additionally, acetazolamide-treated mice showed decreased lung metastasis. Conclusion These findings suggest that due to their effect on blood vessel maturity, pH regulators like CAII are promising targets of antiangiogenic therapy. Graphical abstract

scholarly journals Control of proliferation of human vascular endothelial cells. Characterization of the response of human umbilical vein endothelial cells to fibroblast growth factor, epidermal growth factor, and thrombin

1978 ◽  
Vol 77 (3) ◽  
pp. 774-788 ◽  
Author(s):  
D Gospodarowicz ◽  
KD Brown ◽  
CR Birdwell ◽  
BR Zetter
Keyword(s):  
Endothelial Cells ◽  
Growth Factors ◽  
Growth Factor ◽  
Vascular Endothelial Cells ◽  
Umbilical Vein ◽  
Physiological Role ◽  
Cell Types ◽  
Vascular Endothelial ◽  
Human Endothelial Cells ◽  
Epidermal Growth

Because the response of human endothelial cells to growth factors and conditioning agents has broad implications for our understanding of wound healing angiogenesis, and human atherogenesis, we have investigated the responses of these cells to the fibroblast (FGF) and epidermal growth factors (EGF), as well as to the protease thrombin, which has been previously shown to potentiate the growth response of other cell types of FGF and EGF. Because the vascular endothelial cells that form the inner lining of blood vessels may be expected to be exposed to high thrombin concentrations after trauma or in pathological states associated with thrombosis, they are of particular interest with respect to the physiological role of this protease in potentiating cell proliferation. Our results indicate that human vascular endothelial cells respond poorly to either FGF or thrombin alone. In contrast, when cells are maintained in the presence of thrombin, their proliferative response to FGF is greatly increased even in cultures seeded at a density as low as 3 cells/mm2. Human vascular endothelial cells also respond to EGF and thrombin, although their rate of proliferation is much slower than when maintained with FGF and thrombin. In contrast, bovine vascular endothelial cells derived from vascular territories as diverse as the bovine heart, aortic arch, and umbilical vein respond maximally to FGF alone and neither respond to nor bind EGF. Furthermore, the response of bovine vascular endothelial cells to FGF was not potentiated by thrombin, indicating that the set of factors controlling the proliferation of vascular endothelial cells could be species-dependent. The requirement of cultured human vascular endothelial cells for thrombin could explain why the human cells, in contrast to bovine endothelial cells, are so difficult to maintain in tissue culture. Our results demonstrate that by using FGF and thrombin one can develop cultures of human vascular endothelial cells capable of being passage repeatedly while maintaining a high mitotic index. The stock cultures used for these studies have been passed weekly with a split ratio of 1 to 10 and are currently in their 30th passage. These cultures are indistinguishable from earlier passages when examined for the presence of Weibel-Palade bodies or Factor VIII antigen. We conclude that the use of FGF and thrombin can prevent the precocious senescence observed in most human endothelial cells cultures previously described.

P2X4 receptors mediate ATP-induced calcium influx in human vascular endothelial cells

2000 ◽  
Vol 279 (1) ◽  
pp. H285-H292 ◽  
Author(s):  
Kimiko Yamamoto ◽  
Risa Korenaga ◽  
Akira Kamiya ◽  
Zhi Qi ◽  
Masahiro Sokabe ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Molecular Mechanisms ◽  
Calcium Influx ◽  
Vascular Endothelial Cells ◽  
Umbilical Vein ◽  
Vascular Endothelial ◽  
Protein Levels ◽  
Vasoactive Substances ◽  
Intracellular Ca ◽  
P2x4 Receptors

ATP induces Ca2+ influx across the cell membrane and activates release from intracellular Ca2+ pools in vascular endothelial cells (ECs). Ca2+ signaling leads to the modification of a variety of EC functions, including the production of vasoactive substances such as nitric oxide and prostacyclin. However, the molecular mechanisms for ATP-induced Ca2+ influx in ECs have not been thoroughly clarified. Here we demonstrate evidence that a P2X4receptor for an ATP-gated cation channel is predominantly expressed in human ECs and is involved in the ATP-induced Ca2+ influx. Northern blot analysis distinctly showed the expression of P2X4 mRNA in human ECs cultured from the umbilical vein, aorta, pulmonary artery, and skin microvessels. Competitive PCR revealed that P2X4 mRNA expression was much higher in ECs than was the expression of other subtypes, including P2X1, P2X3, P2X5, and P2X7. Treatment of ECs with antisense oligonucleotides designed to target the P2X4 receptor decreased the P2X4 mRNA and protein levels to ∼25% of control levels and markedly prevented the ATP-induced Ca2+ influx.

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