A Novel Snake Venom Vascular Endothelial Growth Factor (VEGF) Predominantly Induces Vascular Permeability through Preferential Signaling via VEGF Receptor-1

Takahashi, Hiroyuki; Hattori, Satoshi; Iwamatsu, Akihiro; Takizawa, Hajime; Shibuya, Masabumi

doi:10.1074/jbc.m403687200

Cited by 95 publications

(63 citation statements)

References 43 publications

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“…36 On the other hand, another VEGF-like protein (T.f.svVEGF) specifically expressed in the venom of the habu snake increases vascular permeability, most likely for the rapid distribution of toxins in prey. 37 These results further support that VEGF-VEGFR is a crucial system for regulating angiogenesis and vascular permeability and is widely used not only in animals but also in viruses.…”

Section: Other Vegf-like Moleculessupporting

confidence: 65%

Tyrosine Kinase Receptor Flt/VEGFR Family: Its Characterization Related to Angiogenesis and Cancer

Shibuya

2010

Genes & Cancer

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Ligands and their tyrosine kinase (TK) receptors regulate a variety of biological systems in animals. Vascular endothelial growth factor (VEGF) and its receptor (Flt/VEGFR family) system play a crucial role not only in physiological but also in most parts of pathological angiogenesis including cancer. Flt-1/VEGFR-1 and KDR/VEGFR-2 bind VEGF-A but have different functions on angiogenesis at early embryogenesis: Flt-1 has a negative role by trapping ligands, whereas KDR (Flk1 in mice) exerts a strong positive signal, resulting in a balance in blood vessel formation. At adult stages, however, both VEGFRs contribute to pathological angiogenesis either directly or through stimulation of migration/activation of macrophage lineage cells and stimulate tumor growth, metastasis, and inflammation. VEGFRs activate downstream signaling of the phospholipase Cγ-protein kinase C-MAP kinase pathway but not Ras pathway for cell proliferation. The VEGF-C/D and Flt-4/VEGFR-3 system regulates lymphangiogenesis. Thus, VEGFs as well as these receptor TKs are attractive targets for suppressing pathological angiogenesis.

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Section: Other Vegf-like Moleculessupporting

confidence: 65%

Tyrosine Kinase Receptor Flt/VEGFR Family: Its Characterization Related to Angiogenesis and Cancer

Shibuya

2010

Genes & Cancer

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“…Using specific VEGF receptor agonists and inhibition of VEGFR-1 or VEGFR-2 production by specific antisense oligonucleotides, we found that the VEGF-induced external blood-retinal barrier permeability is mediated through VEGFR-1 and not through VEGFR-2. Takahashi et al [28] reported that Trimeresurus flavoviridis snake venom VEGF induces vascular permeability through VEGFR-1 signalling pathways. In Vegf-a transgenic mice, increased angiogenesis and oedema develop, while in transgenic mice overexpressing only Vegfr-2, angiogenesis without increased vessel permeability was observed [29].…”

Section: Discussionmentioning

confidence: 99%

Placental growth factor-1 and epithelial haemato–retinal barrier breakdown: potential implication in the pathogenesis of diabetic retinopathy

et al. 2006

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Aims/hypothesis Disruption of the retinal pigment epithelial (RPE) barrier contributes to sub-retinal fluid and retinal oedema as observed in diabetic retinopathy. High placental growth factor (PLGF) vitreous levels have been found in diabetic patients. This work aimed to elucidate the influence of PLGF-1 on a human RPE cell line (ARPE-19) barrier in vitro and on normal rat eyes in vivo. Methods ARPE-19 permeability was measured using transepithelial resistance and inulin flux under stimulation of PLGF-1, vascular endothelial growth factor (VEGF)-E and VEGF165. Using RT-PCR, we evaluated the effect of hypoxic conditions or insulin on transepithelial resistance and on PLGF-1 and VEGF receptors. The involvement of mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK, also known as EPHB2) signalling pathways under PLGF-1 stimulation was evaluated by western blot analysis and specific inhibitors. The effect of PLGF-1 on the external haemato-retinal barrier was evaluated after intravitreous injection of PLGF-1 in the rat eye; evaluation was by semi-thin analysis and zonula occludens-1 immunolocalisation on flat-mounted RPE. Results In vitro, PLGF-1 induced a reversible decrease of transepithelial resistance and enhanced tritiated inulin flux. These effects were specifically abolished by an antisense oligonucleotide directed at VEGF receptor 1. Exposure of ARPE-19 cells to hypoxic conditions or to insulin induced an upregulation of PLGF-1 expression along with increased transcellular permeability. The PLGF-1-induced RPE cell permeability involved the MEK signalling pathway. Injection of PLGF-1 into the rat eye vitreous induced an opening of the RPE tight junctions with subsequent sub-retinal fluid accumulation, retinal oedema and cytoplasmic translocation of junction proteins. Conclusions/interpretation Our results indicate that PLGF-1 may be a potential regulation target for the control of diabetic retinal and macular oedema.

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“…In addition, a novel snake venom VEGF has been shown to induce vascular permeability through preferential signaling via VEGFR-1. 25 Another major difference observed between VEGF-B and PlGF was the lack of inflammatory cell recruitment into skeletal or cardiac muscle by VEGF-B. In previous work, the recruitment of bone marrow-derived cells, mainly monocytes/macrophages, correlated with arteriogenesis, 2 and this required the neuropilin-1-binding domain of VEGF.…”

Section: Discussionmentioning

confidence: 99%

Vascular Endothelial Growth Factor-B Acts as a Coronary Growth Factor in Transgenic Rats Without Inducing Angiogenesis, Vascular Leak, or Inflammation

et al. 2010

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Background— Vascular endothelial growth factor-B (VEGF-B) binds to VEGF receptor-1 and neuropilin-1 and is abundantly expressed in the heart, skeletal muscle, and brown fat. The biological function of VEGF-B is incompletely understood. Methods and Results— Unlike placenta growth factor, which binds to the same receptors, adeno-associated viral delivery of VEGF-B to mouse skeletal or heart muscle induced very little angiogenesis, vascular permeability, or inflammation. As previously reported for the VEGF-B 167 isoform, transgenic mice and rats expressing both isoforms of VEGF-B in the myocardium developed cardiac hypertrophy yet maintained systolic function. Deletion of the VEGF receptor-1 tyrosine kinase domain or the arterial endothelial Bmx tyrosine kinase inhibited hypertrophy, whereas loss of VEGF-B interaction with neuropilin-1 had no effect. Surprisingly, in rats, the heart-specific VEGF-B transgene induced impressive growth of the epicardial coronary vessels and their branches, with large arteries also seen deep inside the subendocardial myocardium. However, VEGF-B, unlike other VEGF family members, did not induce significant capillary angiogenesis, increased permeability, or inflammatory cell recruitment. Conclusions— VEGF-B appears to be a coronary growth factor in rats but not in mice. The signals for the VEGF-B–induced cardiac hypertrophy are mediated at least in part via the endothelium. Because cardiomyocyte damage in myocardial ischemia begins in the subendocardial myocardium, the VEGF-B–induced increased arterial supply to this area could have therapeutic potential in ischemic heart disease.

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A Novel Snake Venom Vascular Endothelial Growth Factor (VEGF) Predominantly Induces Vascular Permeability through Preferential Signaling via VEGF Receptor-1

Cited by 95 publications

References 43 publications

Tyrosine Kinase Receptor Flt/VEGFR Family: Its Characterization Related to Angiogenesis and Cancer

Tyrosine Kinase Receptor Flt/VEGFR Family: Its Characterization Related to Angiogenesis and Cancer

Placental growth factor-1 and epithelial haemato–retinal barrier breakdown: potential implication in the pathogenesis of diabetic retinopathy

Vascular Endothelial Growth Factor-B Acts as a Coronary Growth Factor in Transgenic Rats Without Inducing Angiogenesis, Vascular Leak, or Inflammation

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