Characterization of murine Flt4 ligand/VEGF-C

Fitz, Lori; Morris, John C.; Towler, Paul; Long, Andrew J.; Burgess, P. R.; Greco, Rita; Wang, Jack; Gassaway, Rob; Nickbarg, Elliott; Kovacic, Sharlotte; Ciarletta, A.; Giannotti, JoAnn; Finnerty, Heather; Zollner, Richard; Beier, David R.; Leak, Lee V.; Turner, Katherine J.; Wood, Clive R.

doi:10.1038/sj.onc.1201191

Cited by 42 publications

(22 citation statements)

References 9 publications

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“…VEGF-C mRNA has been detected by RNase protection assay in adult human kidney (13) and by Northern blotting in rat (24) and mouse (9,25) kidney. Relatively high levels of VEGF-D expression were detected in rat kidney by Northern blotting (24) and in situ hybridization also revealed renal expression of VEGF-D mRNA in young adult mice (8).…”

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confidence: 99%

VEGF-C promotes survival in podocytes

Foster¹,

Satchell²,

Seckley³

et al. 2006

American Journal of Physiology-Renal Physiology

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Vascular endothelial growth factor (VEGF)-A is an autocrine survival factor for podocytes, which express two VEGF receptors, VEGF-R1 and VEGF-R3. As VEGF-A is not a known ligand for VEGF-R3, the aim of this investigation was to examine whether VEGF-C, a known ligand for VEGF-R3, served a function in podocyte biology and whether this was VEGF-R3 dependent. VEGF-C protein expression was localized to podocytes in contrast to VEGF-D, which was expressed in parietal epithelial cells. Intracellular calcium ([Ca2+]i) experiments demonstrated that VEGF-C induced a 0.74 ± 0.09-fold reduction in [Ca2+]i compared with baseline in human conditionally immortalized podocytes (hCIPs; P < 0.05, one sample t-test, n = 8). Cytotoxicity experiments revealed that in hCIPs VEGF-C reduced cytotoxicity to 81.4 ± 1.9% of serum-starved conditions ( P < 0.001, paired t-test, n = 16), similar to VEGF-A (82.8 ± 4.5% of serum-starved conditions, P < 0.05, paired t-test). MAZ51 (a VEGF-R3 kinase inhibitor) inhibited the VEGF-C-induced reduction in cytotoxicity (106.2 ± 2.1% of serum-starved conditions), whereas MAZ51 by itself had no cytotoxic effects on hCIPs. VEGF-C was also shown to induce a 0.5 ± 0.13-fold reduction in levels of MAPK phosphorylation compared with VEGF-A and VEGF-A-Mab treatment ( P < 0.05, ANOVA, n = 4), yet had no effect on Akt phosphorylation. Surprisingly, immunoprecipitation studies detected no VEGF-C-induced autophosphorylation of VEGF-R3 in hCIPs but did so in HMVECs. Moreover, SU-5416, a tyrosine kinase inhibitor, blocked the VEGF-C-induced reduction in cytotoxicity (106 ± 2.8% of serum-starved conditions) at concentrations specific for VEGF-R1. Together, these results suggest for the first time that VEGF-C acts in an autocrine manner in cultured podocytes to promote survival, although the receptor or receptor complex activated has yet to be elucidated.

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mentioning

confidence: 99%

VEGF-C promotes survival in podocytes

Foster¹,

Satchell²,

Seckley³

et al. 2006

American Journal of Physiology-Renal Physiology

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“…Binding of VEGF-C to VEGFR-2 or VEGFR-3 induces tyrosine autophosphorylation of the cytoplasmic tail of its receptors [14]. The VEGF-C gene has been identified on the Chromosome 4q34 in humans and Chromosome 8 in mice [15,16]. VEGF-C is comprised of over 40 kilobase pairs of genomic DNA and its coding sequence resides on all seven exons [17].…”

Section: Characteristics Of Vegf-cmentioning

confidence: 99%

The Role of the VEGF-C/VEGFRs Axis in Tumor Progression and Therapy

Chen

Chang²,

Hong

et al. 2012

IJMS

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Vascular endothelial growth factor C (VEGF-C) has been identified as a multifaceted factor participating in the regulation of tumor angiogenesis and lymphangiogenesis. VEGF-C is not only expressed in endothelial cells, but also in tumor cells. VEGF-C signaling is important for progression of various cancer types through both VEGF receptor-2 (VEGFR-2) and VEGF receptor-3 (VEGFR-3). Likewise, both receptors are expressed mainly on endothelial cells, but also expressed in tumor cells. The dimeric VEGF-C undergoes a series of proteolytic cleavage steps that increase the protein binding affinity to VEGFR-3; however, only complete processing, removing both the N- and C-terminal propeptides, yields mature VEGF-C that can bind to VEGFR-2. The processed VEGF-C can bind and activate VEGFR-3 homodimers and VEGFR-2/VEGFR-3 heterodimers to elicit biological responses. High levels of VEGF-C expression and VEGF-C/VEGFRs signaling correlate significantly with poorer prognosis in a variety of malignancies. Therefore, the development of new drugs that selectively target the VEGF-C/VEGFRs axis seems to be an effective means to potentiate anti-tumor therapies in the future.

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“…In quail and chick embryos, VEGF-C has been observed in areas that become rich in lymphatic endothelium (Eichmann et al 1993(Eichmann et al , 1998. In adult mice, the expression of VEGF-C decreases, but its mRNA can still be found in the lung, heart, liver, and kidney Fitz et al 1997;Lymboussaki et al 1999).…”

Section: Vegf-c Expression and Its Regulationmentioning

confidence: 99%

Genesis and pathogenesis of lymphatic vessels

Jeltsch

Tammela

Alitalo

et al. 2003

Cell and Tissue Research

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The lymphatic system is generally regarded as supplementary to the blood vascular system, in that it transports interstitial fluid, macromolecules, and immune cells back into the blood. However, in insects, the open hemolymphatic (or lymphohematic) system ensures the circulation of immune cells and interstitial fluid through the body. The Drosophila homolog of the mammalian vascular endothelial growth factor receptor (VEGFR) gene family is expressed in hemocytes, suggesting a close relationship to the endothelium that develops later in phylogeny. Lymph hearts are typical organs for the propulsion of lymph in lower vertebrates and are still transiently present in birds. The lymphatic endothelial marker VEGFR-3 is transiently expressed in embryonic blood vessels and is crucial for their development. We therefore regard the question of whether the blood vascular system or the lymphatic system is primary or secondary as open. Future molecular comparisons should be performed without any bias based on the current prevalence of the blood vascular system over the lymphatic system. Here, we give an overview of the structure, function, and development of the lymphatics, with special emphasis on the recently discovered lymphangiogenic growth factors.

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Characterization of murine Flt4 ligand/VEGF-C

Cited by 42 publications

References 9 publications

VEGF-C promotes survival in podocytes

VEGF-C promotes survival in podocytes

The Role of the VEGF-C/VEGFRs Axis in Tumor Progression and Therapy

Genesis and pathogenesis of lymphatic vessels

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