4-(2-Butyl-6,7-dichloro-2-cyclopentyl-indan-1-on-5-yl) oxobutyric acid inhibits angiogenesis via modulation of vascular endothelial growth factor receptor 2 signaling pathway
Tianli ZhouYun‐Da LiHeqiang ZhangLei PanJinglong PangQian YuanGuiyang LiLing‐Jun JieYan WangYanhui Zhang
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Abstract:
4-(2-Butyl-6,7-dichloro-2-cyclopentyl-indan-1-on-5-yl) oxobutyric acid (DCPIB), was discovered to be a potent and specific antagonist of volume-regulated anion channel that is closely linked to angiogenesis. However, the effect of DCPIB on angiogenesis remains unclear. Here, we found that DCPIB inhibited angiogenesis in the corneal suture and myocardial infarction in vivo model. In addition, DCPIB inhibited human umbilical vein endothelial cell migration, tube formation and proliferation in vitro . Moreover, DCPIB repressed the activation and expression of vascular endothelial growth factor receptor 2 (VEGFR2) and its downstream signaling pathway. Computer modeling further confirmed that DCPIB binds with high affinity to VEGFR2. Collectively, we present evidence supporting an antiangiogenic role of DCPIB by targeting VEGFR2 signaling pathway, which suggests that DCPIB is a valuable lead compound for the treatment of angiogenesis-related diseases.Keywords:
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Hypoxia inducible factor-1alpha(HIF-1α) is a major transcription factor that widely exists in mammal and human body in case of hypoxia. HIF-1α activates target genes to transcript and makes the organisms to adapt the hypoxic microenvionment. Also it plays key roles in tumor angiogenesis. Vascular endothelial growth factor(VEGF) is an important target gene of HIF-1α and the receptor KDR is a crucial receptor of VEGF. In recent years a large amount of studies indicate that HIF-1α, VEGF, KDR proteins in a variety of tumors shows high expression and positively associated with each other. Here we make a review of HIF-1α, VEGF, KDR for their molecular biology, their functions in tumor functions and the reseach progress in gynecological tumors.
Hypoxia-Inducible Factors
HIF1A
Hypoxia
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We previously showed that endothelial epsin deficiency caused elevated vascular endothelial growth factor receptor 2 (VEGFR2) and enhanced VEGF signaling, resulting in aberrant tumor angiogenesis and reduced tumor growth in adult mice. However, direct evidence demonstrating that endothelial epsins regulate angiogenesis specifically through VEGFR2 downregulation is still lacking. In addition, whether the lack of epsins causes abnormal angiogenesis during embryonic development remains unclear.A novel strain of endothelial epsin-deleted mice that are heterozygous for VEGFR2 (Epn1(fl/fl); Epn2(-/-); Flk(fl/+); iCDH5 Cre mice) was created. Analysis of embryos at different developmental stages showed that deletion of epsins caused defective embryonic angiogenesis and retarded embryo development. In vitro angiogenesis assays using isolated primary endothelial cells (ECs) from Epn1(fl/fl); Epn2(-/-); iCDH5 Cre (EC-iDKO) and Epn1(fl/fl); Epn2(-/-); Flk(fl/+); iCDH5 Cre (EC-iDKO-Flk(fl/+)) mice demonstrated that VEGFR2 reduction in epsin-depleted cells was sufficient to restore normal VEGF signaling, EC proliferation, EC migration, and EC network formation. These findings were complemented by in vivo wound healing, inflammatory angiogenesis, and tumor angiogenesis assays in which reduction of VEGFR2 was sufficient to rescue abnormal angiogenesis in endothelial epsin-deleted mice.Our results provide the first genetic demonstration that epsins function specifically to downregulate VEGFR2 by mediating activated VEGFR2 internalization and degradation and that genetic reduction of VEGFR2 level protects against excessive angiogenesis caused by epsin loss. Our findings indicate that epsins may be a potential therapeutic target in conditions in which tightly regulated angiogenesis is crucial, such as in diabetic wound healing and tumors.
Angiogenesis inhibitor
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Purpose To detect the expression and significance of vascular endothelial growth factor(VEGF) and vascular endothelial growth factor receptor 2(VEGFR?2) in rat model of emphysema. Methods The rat model of emphysema was established by intratracheal instillation of lipopolysaccharides and cigarette smoke exposure.The localization of VEGF in lungs was detected by immunohistochemistry,the concentration of VEGF in bronchoalveolar lavage fluid(BALF) was measured by ELISA and the expression of VEGFR?2 protein was measured by Western blot. Results VEGF was localized in the alveolar epithelial cells, bronchial mucosal epithelial cells and vascular endothelial cells.The level of VEGF in BALF of model group was significantly decreased(1 102±460.1)pg/mL than that of control group(2 017±840.6)pg/mL(P0.05).Compared with the control group,the expression of VEGFR?2 protein in model group was significantly reduced(P0.05). Conclusions The reduction of VEGF and VEGFR?2 may be related to the pathogenesis of emphysema.
Pathogenesis
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Objective To determine the effect of PTK787 on the expression of vascular endothelial growth factor and vascular endothelial growth factor receptor-2 mRNA,and further discuss the role of PTK787 on anti-acute myeloid leukemia.Methods The acute myeloid leukemia model was established on 40 severe combined immunodeficiency mice by HL-60 cells transplantation.The mice were divided into five group randomly,the normal group,the sicken group,the treated group with 50mg/kg PTK787,the treated group with 100mg/kg PTK787,the treated group with 200mg/kg PTK787.Logarithmic phase cells were implanted into the sicken group and the treated group by celiac injection.The expression of vascular endothelial growth factor was detected by enzyme linked immunosorbent assay.The expression of vascular endothelial growth factor receptor-2 mRNA was detected by reverse transcription-polymerase chain reaction.Results(1)Expression of vascular endothelial growth factors and vascular endothelial growth factor receptor-2 mRNA were determined on all mice.(2)Compared with the normal group,the mRNA level of vascular endothelial growth factor and vascular endothelial growth factor receptor-2 in the sicken group was significantly and gradually increased with the course of disease.(3)Compared with the sicken group,the expression of vascular endothelial growth factor and vascular endothelial growth factor receptor-2 mRNA of treated group decreased obviously.Conclusion The anti-effect on acute myeloid leukemia of PTK787 is related with the decrease expression of vascular endothelial growth factor and vascular endothelial growth factor receptor-2.
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AIM:To observe the expression of vascular endothelial growth factor,tumor necrosis factor α(TNF-α),vascular endothelial growth factor receptor-proteinum 1,vascular endothelial growth factor receptor-proteinum 2,tumor necrosis factor-α receptor-proteinum 5500 kD(P55) and tumor necrosis factor-α receptor-proteinum 7500 kD(P75) in nasopharyngeal carcinoma,and analyze dependability of those cell factor.METHODS:Sixty tissues of nasopharyngeal carcinoma were stained with immunizing histological chemistry way,expression of VEGF,TNF-α,VEGFR1,VEGFR2,P55,P75 were measured,and analysize the dependability.RESULTS:VEGF,TNF-α,VEGFR1,VEGFR2,P55 and P75 were expressed in tissues of nasopharyngeal carcinoma,there were positive dependability between VEGF and VEGFR1,VEGF and VEGFR2,TNF-α and P55(r=0.442,P=0.002),VEGF and TNF-α.CONCLUSION:TNF-α,P55 and P75 had an over expression in tissues of nasopharyngeal carcinoma.VEGF and TNF-α maybe nasopharyngeal carcinoma to nasopharyngeal carcinoma by mutual control to receptor protein.
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Preeclampsia (PE) is the leading cause of maternal and fetal morbidity and mortality. It complicates around 2%–10% pregnancies worldwide due to imbalance between proangiogenic and anti-angiogenic factors, leading to incomplete placentation, ischemia, and endothelial dysfunction. The study was aimed to analyze the mRNA expression of vascular endothelial growth factor (VEGF) and its receptors, i.e., VEGF receptor-1 (VEGFR-1), VEGF receptor-2 (VEGFR-2), and soluble Fms-like tyrosine kinase-1 (sFlt-1) from maternal peripheral blood mononuclear cells (PBMCs) of PE patients. This was a cross-sectional comparative study comprising 18 normotensive and 18 PE patients; the patients were further divided as early-onset preeclampsia (EOP) and late-onset preeclampsia (LOP). The expression level of VEGF, its receptors (VEGFR-1 and VEGFR-2), and sFlt-1 was investigated using real-time polymerase chain reaction. There was a significant change in the mRNA expression with a decrease in VEGF, VEGFR-1, and VEGFR-2 and an increase in sFlt-1 in PBMCs of PE and normal pregnancies ( P < 0.001). sFlt-1 mRNA expression was increased by 2.95-fold in the PE group with an inverse correlation with expression of VEGFR-2 (Spearman's rho = 0.68). Based on these findings, we conclude that PE is associated with decrease in the mRNA expression of VEGF, VEGFR-1, and VEGFR-2 as compared to an increase in sFlt-1 in PBMCs.
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Vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9) are mediators of airway inflammation and remodeling in asthma.This study investigates a potential relationship between VEGF and MMP-9, and the mechanisms by which VEGF signaling regulates MMP-9 expression in asthma.We evaluated whether levels of VEGF correlated with levels of MMP-9 in the sputum of asthma patients, and the effect of VEGF receptor inhibitors on MMP-9 expression in murine model of asthma.We have found that levels of VEGF and MMP-9 are significantly higher in the sputum of patients with asthma than in healthy control subjects, and a significant correlation is found between the levels of VEGF and MMP-9. This study with the ovalbumin-induced model of asthma revealed the following typical pathophysiologic features of asthma in the lungs: increased numbers of inflammatory cells of the airways, airway hyperresponsiveness, increased vascular permeability, and increased levels of MMP-9 and VEGF. Administration of VEGF receptor inhibitors reduced the pathophysiologic signs of asthma and decreased the increased expression of MMP-9 after ovalbumin inhalation.These results indicate that there is a close relationship between VEGF and MMP-9 expression and that inhibition of VEGF receptor down-regulates the expression of MMP-9. These findings suggest that VEGF signaling regulates MMP-9 expression and plays a critical role in initiation and maintenance of asthma.
Pathophysiology
Vascular permeability
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Background:Blocking vascular endothelial growth factor receptor (VEGFR) is a successful approach for inhibiting vascular endothelial growth factor (VEGF) signaling. Small molecules impairing the interaction of VEGF with VEGF receptors have been synthesized and evaluated in this research.
Blocking (statistics)
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