Signal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesis

Shibuya, Masabumi; Claesson‐Welsh, Lena

doi:10.1016/j.yexcr.2005.11.012

Cited by 930 publications

(716 citation statements)

References 109 publications

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“…Vascular endothelial growth factor-A interacts with both VEGFR-1 and VEGFR-2 to mediate angiogenesis, whereas VEGF-B and PlGF have high affinity for only VEGFR-1. Vascular endothelial growth factor-C and VEGF-D bind both VEGFR-2 and VEGFR-3 (Joukov et al, 1996;Achen et al, 1998) to regulate angiogenesis and have been implicated in lymphangiogenesis (Shibuya and Claesson-Welsh, 2006). Vascular endothelial growth factor receptor-2 is the principal receptor that promotes the pro-angiogenic action of VEGF-A and has been the principal target of anti-angiogenic therapies, although additional studies have underlined the importance of signalling through VEGFR-1 (Carmeliet et al, 2001).…”

Section: Vascular Endothelial Growth Factormentioning

confidence: 99%

Biomarkers of angiogenesis and their role in the development of VEGF inhibitors

2009

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Vascular endothelial growth factor (VEGF) has been confirmed as an important therapeutic target in randomised clinical trials in multiple disease settings. However, the extent to which individual patients benefit from VEGF inhibitors is unclear. If we are to optimise the use of these drugs or develop combination regimens that build on this efficacy, it is critical to identify those patients who are likely to benefit, particularly as these agents can be toxic and are expensive. To this end, biomarkers have been evaluated in tissue, in circulation and by imaging. Consistent drug-induced increases in plasma VEGF-A and blood pressure, as well as reductions in soluble VEGF-R2 and dynamic contrast-enhanced MRI parameters have been reported. In some clinical trials, biomarker changes were statistically significant and associated with clinical end points, but there is considerable heterogeneity between studies that are to some extent attributable to methodological issues. On the basis of observations with these biomarkers, it is now appropriate to conduct detailed prospective studies to define a suite of predictive, pharmacodynamic and surrogate response biomarkers that identify those patients most likely to benefit from and monitor their response to this novel class of drugs.

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Section: Vascular Endothelial Growth Factormentioning

confidence: 99%

Biomarkers of angiogenesis and their role in the development of VEGF inhibitors

2009

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“…VEGF functions are mediated by three VEGF receptors (VEGFR-1, VEGFR-2, and VEGFR-3) expressed in HUVECs, but previous work has shown that the VEGFR-2 is the main receptor responsible for processes such as cell migration [7,[20][21][22]. To examine the role of this receptor in VEGF signaling to Rac1, we first used two structurally different but selective VEGFR-2 inhibitors, SU1498 and ZM323881.…”

Section: Vegf Activates Rac1 Through Vegfr-2 In Endothelial Cellsmentioning

confidence: 99%

VEGF-induced Rac1 activation in endothelial cells is regulated by the guanine nucleotide exchange factor Vav2

Garrett

Buul

Burridge

2007

Experimental Cell Research

152

132

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Vascular endothelial growth factor (VEGF) signaling is critical for both normal and diseaseassociated vascular development. Dysregulated VEGF signaling has been implicated in ischemic stroke, tumor angiogenesis, and many other vascular diseases. VEGF signals through several effectors, including the Rho family of small GTPases. As a member of this family, Rac1 promotes VEGF-induced endothelial cell migration by stimulating the formation of lamellipodia and membrane ruffles. To form these membrane protrusions, Rac1 is activated by guanine nucleotide exchange factors (GEFs) that catalyze the exchange of GDP for GTP. The goal of this study was to identify the GEF responsible for activating Rac1 in response to VEGF stimulation. We have found that VEGF stimulates biphasic activation of Rac1 and for these studies we focused on the peak of activation that occurs at 30 min. Inhibition of VEGFR-2 signaling blocks VEGF-induced Rac1 activation. Using a Rac1 nucleotide-free mutant (G15ARac1), which has a high affinity for binding activated GEFs, we show that the Rac GEF Vav2 associates with G15ARac1 after VEGF stimulation. Additionally, we show that depleting endothelial cells of endogenous Vav2 with siRNA prevents VEGF-induced Rac1 activation. Moreover, Vav2 is tyrosine phosphorylated upon VEGF treatment, which temporally correlates with Rac1 activation and requires VEGFR-2 signaling and Src kinase activity. Finally, we show that depressing Vav2 expression by siRNA impairs VEGF-induced endothelial cell migration. Taken together, our results provide evidence that Vav2 acts downstream of VEGF to activate Rac1.

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“…There are three known VEGF receptors: VEGFR1/fmsrelated tyrosine kinase 1 (Flt1), VEGFR2/kinase insert domain receptor (KDR), and Neuropilin-1 [19] . VEGF elicits its biological functions by activating specific transmembrane receptors (VEGFR1 and VEGFR2) with intrinsic tyrosine kinase activity [20] . Neuropilin-1 has no tyrosine kinase activity.…”

Section: Introductionmentioning

confidence: 99%

Blocking VEGF/Caveolin-1 signaling contributes to renal protection of fasudil in streptozotocin-induced diabetic rats

Jin

Peng

et al. 2015

Acta Pharmacol Sin

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Aim: RhoA/ROCK signaling plays an important role in diabetic nephropathy, and ROCK inhibitor fasudil exerts nephroprotection in experimental diabetic nephropathy. In this study we investigated the molecular mechanisms underlying the protective actions of fasudil in a rat model of diabetic nephropathy. Methods: Streptozotocin (STZ)-induced diabetic rats, to which fasudil or a positive control drug enalapril were orally administered for 8 months. Metabolic parameters and blood pressure were assessed during the treatments. After the rats were euthanized, kidney samples were collected for histological and molecular biological studies. VEGF, VEGFR1, VEGFR2 and fibronectin expression, and Src and caveolin-1 phosphorylation in the kidneys were assessed using RT-PCR, Western blot and immunohistochemistry assays. The association between VEGFR2 and caveolin-1 was analyzed with immunoprecipitation. Results: Chronic administration of fasudil (30 and 100 mg·kg -1 ·d -1 ) or enalapril (10 mg/kg, bid) significantly attenuated the glomerular sclerosis and albuminuria in the diabetic rats. Furthermore, fasudil treatment prevented the upregulation of VEGF, VEGFR1, VEGFR2 and fibronectin, and the increased association between VEGFR2 and caveolin-1 in the renal cortices, and partially blocked Src activation and caveolin-1 phosphorylation on tyrosine 14 in the kidneys, whereas enalapril treatment had no effects on the VEGFR2/ Src/caveolin-1 signaling pathway. Conclusion: Fasudil exerts protective actions in STZ-induced diabetic nephropathy by blocking the VEGFR2/Src/caveolin-1 signaling pathway and fibronectin upregulation. Thus, VEGFR2 may be a potential therapeutic target for the treatment of diabetic nephropathy.

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Signal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesis

Cited by 930 publications

References 109 publications

Biomarkers of angiogenesis and their role in the development of VEGF inhibitors

Biomarkers of angiogenesis and their role in the development of VEGF inhibitors

VEGF-induced Rac1 activation in endothelial cells is regulated by the guanine nucleotide exchange factor Vav2

Blocking VEGF/Caveolin-1 signaling contributes to renal protection of fasudil in streptozotocin-induced diabetic rats

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