Roles of two VEGF receptors, Flt-1 and KDR, in the signal transduction of VEGF effects in human vascular endothelial cells

Kanno, Satoshi; Oda, Noriichi; Abé, Mayumi; Terai, Yoshito; Ito, Mikito; Shitara, Kenya; Tabayashi, Koichi; Shibuya, Masabumi; Sato, Yasufumi

doi:10.1038/sj.onc.1203533

Cited by 265 publications

(192 citation statements)

References 35 publications

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“…Another report suggests that VEGFR-1 might be important for endothelial cell migration. Indeed, VEGFR-1 blocking antibodies prevented migration but not proliferation of human umbilical vein endothelial (HUVE) cells in response to VEGF (Kanno et al, 2000). In the same study the VEGFR-1-mediated signal appeared to modulate preferentially actin reorganization via the p38 MAP kinase, whereas VEGFR-2 contributed to the reorganization of the cytoskeleton by phosphorylating FAK and paxillin, thus suggesting a di erential contribution of the two receptors to the chemotactic response.…”

Section: Vegfr-1mentioning

confidence: 83%

“…However, based on studies of cell lines expressing individual receptors or employing ligands speci®c for only one receptor type, the current view is that VEGFR-2 is a major receptor transducing the e ects of VEGF into endothelial cells (see Figure 2). For example, similar to VEGF, viral homologues VEGF-E that bind and activate only VEGFR-2, can stimulate the release of tissue factor, proliferation, chemotaxis and sprouting of cultured vascular endothelial cells in vitro and angiogenesis in vivo (Meyer et al, 1999;Wise et al, 1999) and VEGFR-2 blocking antibodies prevent DNA synthesis in response to VEGF (Kanno et al, 2000). In several tumor models, angiogenesis is prevented by expression of a dominant negative mutant VEGFR-2 or by use of VEGFR-2 blocking antibodies (Millauer et al, 1994;Skobe et al, 1997).…”

Section: Vegfr-2mentioning

confidence: 99%

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Vascular endothelial growth factor receptors in the regulation of angiogenesis and lymphangiogenesis

2000

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Section: Vegfr-1mentioning

confidence: 83%

Section: Vegfr-2mentioning

confidence: 99%

Vascular endothelial growth factor receptors in the regulation of angiogenesis and lymphangiogenesis

2000

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“…However, p38α deletion results in homozygous embryonic lethality due to reduced vascularization and increased apoptosis (Mudgett et al, 2000), suggesting that p38 provides a positive stimulus to sustain the vasculature. VEGF induced cell migration requires p38 (Kanno et al, 2000) and VEGF induced VEGFR2 dependent p38 phosphorylation is necessary for in vitro tube formation (Yang et al, 2001;Rocic et al, 2007). In vivo, ischemia/reperfusion induced coronary collateral growth is reduced by 50% following p38 inhibition (Rocic et al, 2007), again supporting a pro-angiogenic role for p38 activity.…”

Section: Introductionmentioning

confidence: 91%

p38 MAPK activity is stimulated by vascular endothelial growth factor receptor 2 activation and is essential for shear stress‐induced angiogenesis

Gee

Milkiewicz

Haas

2009

Journal Cellular Physiology

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Increased capillary shear stress induces angiogenesis in skeletal muscle, but the signaling mechanisms underlying this response are not known. We hypothesize that shear stress-dependent activation of vascular endothelial growth factor receptor 2 (VEGFR2) causes p38 and ERK1/2 phosphorylation, which contribute to shear stress-induced angiogenesis. Skeletal muscle microvascular endothelial cells were sheared (12 dynes/cm 2 , 0.5-24 hours). VEGFR2-Y1214 phosphorylation increased in response to elevated shear stress and VEGF stimulation. p38 and ERK1/2 phosphorylation increased at 2 hours of shear stress, but only p38 remained phosphorylated at 6 and 24 hours of shear stress. VEGFR2 inhibition abrogated p38, but not ERK1/2 phosphorylation. VEGF production was increased in response to shear stress at 6 hours, and this increased production was abolished by p38 inhibition. Male Sprague-Dawley rats were administered prazosin (50 mg/L drinking water, 1, 2, 4 or 7 days) to induce chronically elevated capillary shear stress in skeletal muscle. In some experiments, mini-osmotic pumps were used to dispense p38 inhibitor SB203580 or its inactive analog SB202474, to the extensor digitorum longus (EDL) of control and prazosin treated rats. Immunostaining and Western blotting showed increases in p38 phosphorylation in capillaries from rats treated with prazosin for 2 days but returned to basal levels at 4 and 7 days. p38 inhibition abolished the increase in capillary to muscle fibre ratio seen after 7 days of prazosin treatment. Our data suggest that p38 activation is necessary for shear stress-dependent angiogenesis.

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“…Western blotting was performed as described previously. 16 A sample (20 lg) of lysate protein was subjected to SDS-PAGE under reducing conditions. The proteins were then transferred onto PVDF membrane, followed by Western blot analysis.…”

Section: Western Blotting Analysismentioning

confidence: 99%

E7080, a novel inhibitor that targets multiple kinases, has potent antitumor activities against stem cell factor producing human small cell lung cancer H146, based on angiogenesis inhibition

Matsui¹,

Yamamoto²,

Funahashi³

et al. 2007

Intl Journal of Cancer

481

315

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E7080 is an orally active inhibitor of multiple receptor tyrosine kinases including VEGF, FGF and SCF receptors. In this study, we show the inhibitory activity of E7080 against SCF-induced angiogenesis in vitro and tumor growth of SCF-producing human small cell lung carcinoma H146 cells in vivo. E7080 inhibits SCF-driven tube formation of HUVEC, which express SCF receptor, KIT at the IC 50 value of 5.2 nM and it was almost identical for VEGFdriven one (IC 50 5 5.1 nM). To assess the role of SCF/KIT signaling in tumor angiogenesis, we evaluated the effect of imatinib, a selective KIT kinase inhibitor, on tumor growth of H146 cells in nude mice. Imatinib did not show the potent antitumor activity in vitro (IC 50 5 2,200 nM), because H146 cells did not express KIT. However, oral administration of imatinib at 160 mg/kg clearly slowed tumor growth of H146 cells in nude mice, accompanied by decreased microvessel density. Oral administration of E7080 inhibited tumor growth of H146 cells at doses of 30 and 100 mg/kg in a dose-dependent manner and caused tumor regression at 100 mg/kg. While anti-VEGF antibody also slowed tumor growth, it did not cause tumor regression. These results indicate that KIT signaling has a role in tumor angiogenesis of SCF-producing H146 cells, and E7080 causes regression of H146 tumors as a result of antiangiogenic activity mediated by inhibition of both KIT and VEGF receptor signaling. E7080 may provide therapeutic benefits in the treatment of SCF-producing tumors. ' 2007 Wiley-Liss, Inc.

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Roles of two VEGF receptors, Flt-1 and KDR, in the signal transduction of VEGF effects in human vascular endothelial cells

Cited by 265 publications

References 35 publications

Vascular endothelial growth factor receptors in the regulation of angiogenesis and lymphangiogenesis

Vascular endothelial growth factor receptors in the regulation of angiogenesis and lymphangiogenesis

p38 MAPK activity is stimulated by vascular endothelial growth factor receptor 2 activation and is essential for shear stress‐induced angiogenesis

E7080, a novel inhibitor that targets multiple kinases, has potent antitumor activities against stem cell factor producing human small cell lung cancer H146, based on angiogenesis inhibition

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