Utilization of Distinct Signaling Pathways by Receptors for Vascular Endothelial Cell Growth Factor and Other Mitogens in the Induction of Endothelial Cell Proliferation

Wu, Li-Wha; Mayo, Lindsey D.; Dunbar, James D.; Kessler, Kelly M.; Baerwald, Melinda R.; Jaffe, Eric; Wang, Dongfang; Warren, Robert S.; Donner, David B.

doi:10.1074/jbc.275.7.5096

Cited by 266 publications

(223 citation statements)

References 51 publications

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“…The importance of the Raf/MEK/ERK signaling pathway in VEGFmediated angiogenesis is also supported by the finding that Raf-1 has a pivotal role in protecting endothelial cells from extrinsic-mediated apoptosis during angiogenesis (Alavi et al, 2003). In addition, our data are consistent with the finding that PD98059 is able to block the proliferation, migration and tube formation of endothelial cells in vitro (Wu et al, 2000;Srivastava et al, 2009). Intriguingly, the regulatory function of RKTG in angiogenesis is similar to that of Spred-1, which also functions as a negative regulator of Raf kinase by interfering with the phosphorylation and activation of Raf-1 (Wakioka et al, 2001).…”

Section: Discussionsupporting

confidence: 89%

RKTG inhibits angiogenesis by suppressing MAPK-mediated autocrine VEGF signaling and is downregulated in clear-cell renal cell carcinoma

et al. 2010

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Section: Discussionsupporting

confidence: 89%

RKTG inhibits angiogenesis by suppressing MAPK-mediated autocrine VEGF signaling and is downregulated in clear-cell renal cell carcinoma

et al. 2010

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“…We did not observe any changes in VEGFR1 levels, and there was no evidence of VEGFR1 phosphorylation in any of the groups of mice ( Figure 2I). In further confirmation of VEGFR2 activation, we observed elevated Akt phosphorylation, a downstream target of VEGFR2 signaling, 29 after Flk-sel treatment in both WT and eNOSKO mice (Figure 2, J and K). These data suggest that renal VEGFR2 was successfully stimulated by rAAV1-Flk-sel administration in this model.…”

Section: Systemic Overexpression Of Raav1-flk-sel In Wt and Enosko Micesupporting

confidence: 59%

Selective Stimulation of VEGFR2 Accelerates Progressive Renal Disease

Sato

Tanabe

Kosugi

et al. 2011

The American Journal of Pathology

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Vascular endothelial growth factor A (VEGF-A) can play both beneficial and deleterious roles in renal diseases, where its specific function might be determined by nitric oxide bioavailability. The complexity of VEGF-A in renal disease could in part be accounted for by the distinct roles of its two receptors; VEGFR1 is involved in the inflammatory responses, whereas VEGFR2 predominantly mediates angiogenesis. Because nondiabetic chronic renal disease is associated with capillary loss, we hypothesized that selective stimulation of VEGFR2 could be beneficial in this setting. However, VEGFR2 activation may be deleterious in the presence of nitric oxide deficiency. We systematically overexpressed a mutant form of VEGF-A binding only VEGFR2 (Flk-sel) using an adeno-associated virus-1 vector in wild-type and eNOS knockout mice and then induced renal injury by uninephrectomy. Flksel treatment increased angiogenesis and lowered blood pressure in both mouse types. Flk-sel overexpression caused mesangial injury with increased proliferation associated with elevated expression of PDGF, PDGF-␤ receptor, and VEGFR2; this effect was greater in eNOS knockout than in wild-type mice. Flk-sel also induced tubulointerstitial injury, with some tubular epithelial cells expressing ␣-smooth muscle actin, indicating a phenotypic evolution toward myofibroblasts. In conclusion, prestimulation of VEGFR2 can potentiate subsequent renal injury in mice, an effect enhanced in the setting of nitric oxide deficiency.

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“…One likely scenario is that in order for VEGF to upregulate eNOS expression, signaling pathways other than ERK1/2, AKT1 and JNK1/2 need to become activated. For instance, protein kinase C (PKC) activation by VEGF has been shown to be critical for eNOS upregulation in adrenal cortex endothelial cells [9] and in stimulating HUVEC proliferation [30]. It is speculating that a deficiency in PKC and/or phospholipase C that are known for mediating eNOS expression by VEGF in other systems (9) could contribute to the different effects of VEGF and FGF2 on eNOS expression.…”

Section: Discussionmentioning

confidence: 99%

Differential Activation of Multiple Signalling Pathways Dictates eNOS Upregulation by FGF2 but not VEGF in Placental Artery Endothelial Cells

et al. 2008

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Fibroblast growth factor (FGF2), but not vascular endothelial growth factor (VEGF), upregulates endothelial nitric oxide synthase (eNOS) protein expression, at least in part, via activation of extracellular signal-regulated kinase 2/1 (ERK2/1) in ovine fetoplacental artery endothelial (oFPAE) cells. Herein we further investigated the temporal effects of FGF2 and VEGF on other signaling pathways including members (Jun N-terminal kinase JNK1/2 and p38MAPK) of mitogen-activated protein kinases (MAPK), phosphatidylinositol 3 kinase/v-akt murine thymoma viral oncogene homolog 1 (PI3K/AKT1), and the tyrosine kinase c-SRC, and examined if either one or more of these pathways play a role in the differential regulation of eNOS by FGF2 and VEGF. We first confirmed that in oFPAE cells, FGF2, but not VEGF, increased eNOS protein. FGF2 stimulated eNOS protein in a time and concentration dependent manner, which also depended on cell density. FGF2 provoked sustained (5 min to 12 h) whereas VEGF only stimulated transient (5 min) ERK2/1 phosphorylation. FGF2 was 1.7-fold more potent in stimulating ERK2/1 phosphorylation than VEGF. FGF2 and VEGF only transiently activated JNK1/2 and AKT1 within 5 min; however, FGF2 was a stronger stimulus than VEGF. FGF2 and VEGF did not significantly activate p38MAPK at 5 min; however, VEGF stimulated p38MAPK phosphorylation at 60 min. VEGF but not FGF2 significantly stimulated c-SRC phosphorylation. Inhibitors of MEK-ERK2/1 (PD98059), JNK1/2 (SP600125) and PI3K (wortmannin), but not p38MAPK (SB203580) and SRC (PP2), decreased the FGF2-increased eNOS protein expression. Thus, the FGF2-induced eNOS protein expression requires activation of multiple signaling pathways including ERK2/1, JNK1/2 and PI3K/AKT1. Differences in intensity and temporal patterns of activation of these pathways by FGF2 and VEGF may account for their differential effects on eNOS expression in OFPAE cells.

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Utilization of Distinct Signaling Pathways by Receptors for Vascular Endothelial Cell Growth Factor and Other Mitogens in the Induction of Endothelial Cell Proliferation

Cited by 266 publications

References 51 publications

RKTG inhibits angiogenesis by suppressing MAPK-mediated autocrine VEGF signaling and is downregulated in clear-cell renal cell carcinoma

RKTG inhibits angiogenesis by suppressing MAPK-mediated autocrine VEGF signaling and is downregulated in clear-cell renal cell carcinoma

Selective Stimulation of VEGFR2 Accelerates Progressive Renal Disease

Differential Activation of Multiple Signalling Pathways Dictates eNOS Upregulation by FGF2 but not VEGF in Placental Artery Endothelial Cells

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