Heparan Sulfate Proteoglycans Mediate the Angiogenic Activity of the Vascular Endothelial Growth Factor Receptor-2 Agonist Gremlin

Chiodelli, Paola; Mitola, Stefania; Ravelli, Cosetta; Oreste, Pasqua; Rusnati, Marco; Presta, Marco

doi:10.1161/atvbaha.111.235184

Cited by 70 publications

(88 citation statements)

References 59 publications

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“…These data also suggest that rhGrem1 is not binding to and preventing access to the BMP receptors. Previous groups have identified that Grem1 can interact with several cell surface receptors including VEGFR2 and heparin sulphate proteoglycans [43,45]. Our data suggest that these cell surface receptor interactions do not "capture" sufficient Grem1 to allow significant inhibition of BMP signalling in HK-2 cells.…”

Section: Discussionmentioning

confidence: 63%

“…Given the critical role of Grem1 posttranslational processing and glycosylation in its function [43], the ability of Grem1 expression to inhibit BMP action when expressed in mammalian cells was then assessed. After optimization, a protocol was developed whereby > 80 % transfection efficiency was routinely obtained in HEK293 cells using pcDNA3.1A containing the human Grem1 cDNA (Fig.…”

Section: Overexpression Of Human Gremlin1 Inhibits Bmp Signalling In mentioning

confidence: 99%

“…Grem1 has been shown to bind to heparin and heparin sulphate proteoglycans, thus modulating its interaction with the VEGFR2 and subsequent pro-angiogenic activity [43]. Other evidence demonstrated that Grem1 acts intracellularly to regulate BMP-4 activation and secretion [23].…”

Section: Cell-associated Gremlin1 Does Not Inhibit Bmp-mediated Signamentioning

confidence: 99%

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Gremlin1 preferentially binds to bone morphogenetic protein-2 (BMP-2) and BMP-4 over BMP-7

Church

Krishnakumar

Urbanek

et al. 2015

Biochemical Journal

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Section: Discussionmentioning

confidence: 63%

Section: Overexpression Of Human Gremlin1 Inhibits Bmp Signalling In mentioning

confidence: 99%

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Gremlin1 preferentially binds to bone morphogenetic protein-2 (BMP-2) and BMP-4 over BMP-7

Church

Krishnakumar

Urbanek

et al. 2015

Biochemical Journal

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“…Alginate pellets containing 0.1-1.0 pmol per pellet of TR-644 or CA4 were grafted on the chorioallantoic membrane (CAM) of fertilized chicken eggs at day 11 [24]. After 72 h new blood vessels converging toward the implant were counted at 59 magnification under a stereomicroscope.…”

Section: Cam Assay In Fertilized Chicken Eggsmentioning

confidence: 99%

TR-644 a novel potent tubulin binding agent induces impairment of endothelial cells function and inhibits angiogenesis

et al. 2013

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TR-644 is a novel combretastatin A-4 (CA-4) analogue endowed with potent microtubule depolymerizing activity superior to that of the lead compound and it also has high affinity to colchicines binding site of tubulin. We tested TR-644 anti-angiogenic effects in human umbilical endothelial cells (HUVEC). It showed no significant effects on the growth of HUVEC cells at concentrations below 1,000 nM, but at much lower concentrations (10-100 nM) it induced inhibition of capillary tube formation, inhibition of endothelial cell migration and affected endothelial cell morphology as demonstrated by the disruption of the microtubule network. TR-644 also increased permeability of HUVEC cells in a time dependent manner. The molecular mechanism for the anti-vascular activity of TR-644 was investigated in detail. TR-644 caused G2/M arrest in endothelial cells and this effect correlated with downregulation of the expression of Cdc25C and Cdc2Tyr15 .Moreover TR-644 inhibited VEGF-induced phosphorylation of VE-cadherin but did not prevent the VEGF-induced phosphorylation of FAK. In chick chorioallantoic membrane in vivo assay, TR-644 (0.1-1.0 pmol/egg) efficiently counteracted the strong angiogenic response induced by FGF. Also CA-4, used as reference compound, caused an antagonistic effect, but in contrast, it induced per se, a remarkable angiogenic response probably due to an inflammatory reaction in the site of treatment. In a mice allogenic tumor model, immunohistochemical staining of tumors with anti-CD31 antibody showed that TR-644 significantly reduced the number of vessel, after 24 h from the administration of a single dose (30 mg/Kg).

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“…14) and VEGFR2-overexpressing GM7373 cells (GM7373-VEGFR2 cells; ref. 31) were incubated with 60 mmol/L KIN59 or vehicle for 30 minutes, after which 10 ng/mL FGF2 or 30 ng/mL VEGF was added. After 10 minutes of stimulation, cells were lysed and 50 mg aliquots of the cell extracts were analyzed by SDS-PAGE followed by Western blotting with anti-P-FGFR1 antibody (Santa Cruz Biotechnology), anti-p-Akt antibody (Cell Signaling Technology), and anti-p-VEGFR2 antibody (R&D Systems).…”

Section: Western Blot Analysismentioning

confidence: 99%

The Thymidine Phosphorylase Inhibitor 5′-O-Tritylinosine (KIN59) Is an Antiangiogenic Multitarget Fibroblast Growth Factor-2 Antagonist

Liekens

Bronckaers

Belleri

et al. 2012

Molecular Cancer Therapeutics

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is an allosteric inhibitor of the angiogenic enzyme thymidine phosphorylase.Previous observations showed the capacity of KIN59 to abrogate thymidine phosphorylase-induced as well as developmental angiogenesis in the chicken chorioallantoic membrane (CAM) assay. Here, we show that KIN59 also inhibits the angiogenic response triggered by fibroblast growth factor-2 (FGF2) but not by VEGF in the CAM assay. Immunohistochemical and reverse transcriptase PCR analyses revealed that the expression of laminin, the major proteoglycan of the basement membrane of blood vessels, is downregulated by KIN59 administration in control as well as in thymidine phosphorylase-or FGF2-treated CAMs, but not in CAMs treated with VEGF. Also, KIN59 abrogated FGF2-induced endothelial cell proliferation, FGF receptor activation, and Akt signaling in vitro with no effect on VEGF-stimulated biologic responses. Accordingly, KIN59 inhibited the binding of FGF2 to FGF receptor-1 (FGFR1), thus preventing the formation of productive heparan sulphate proteoglycan/FGF2/FGFR1 ternary complexes, without affecting heparin interaction. In keeping with these observations, systemic administration of KIN59 inhibited the growth and neovascularization of subcutaneous tumors induced by FGF2-transformed endothelial cells injected in immunodeficient nude mice. Taken together, the data indicate that the thymidine phosphorylase inhibitor KIN59 is endowed with a significant FGF2 antagonist activity, thus representing a promising lead compound for the design of multitargeted antiangiogenic cancer drugs.

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Heparan Sulfate Proteoglycans Mediate the Angiogenic Activity of the Vascular Endothelial Growth Factor Receptor-2 Agonist Gremlin

Abstract: Objective-Heparan sulfate proteoglycans (HSPGs) modulate the interaction of proangiogenic heparin-binding vascular endothelial growth factors (VEGFs) with signaling VEGF receptor-2 (VEGFR2) and neuropilin coreceptors in endothelial cells (ECs

Cited by 70 publications

References 59 publications

Gremlin1 preferentially binds to bone morphogenetic protein-2 (BMP-2) and BMP-4 over BMP-7

Gremlin1 preferentially binds to bone morphogenetic protein-2 (BMP-2) and BMP-4 over BMP-7

TR-644 a novel potent tubulin binding agent induces impairment of endothelial cells function and inhibits angiogenesis

The Thymidine Phosphorylase Inhibitor 5′-O-Tritylinosine (KIN59) Is an Antiangiogenic Multitarget Fibroblast Growth Factor-2 Antagonist

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