Rho Family GTPases Regulate VEGF-Stimulated Endothelial Cell Motility

Soga, Norihito; Namba, Noriyuki; McAllister, Sandy; Cornelius, Lynn A.; Teitelbaum, Steven L.; Dowdy, Steven F.; Kawamura, J; Hruska, Keith A.

doi:10.1006/excr.2001.5295

Cited by 128 publications

(110 citation statements)

References 64 publications

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“…5C). These findings are consistent with a previous report indicating that transduction of ECs with a Tat-N19Rho fusion protein did not alter migration, but they are not consistent with findings reported in the same manuscript indicating that TatV14Rho inhibited migration (37). However, the Tat-Rho fusion proteins appear to have resulted in greater intracellular concentrations of the Rho mutants relative to those achieved with retrovirus in our experiments, and this may explain the different consequences for EC migration.…”

Section: Resultssupporting

confidence: 81%

Rho activity critically and selectively regulates endothelial cell organization during angiogenesis

Hoang

Whelan

Senger

2004

Proc. Natl. Acad. Sci. U.S.A.

179

187

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The mechanisms that control organization of endothelial cells (ECs) into new blood vessels are poorly understood. We hypothesized that the GTPase Rho, which regulates cytoskeletal architecture, is important for EC organization during neovascularization. To test this hypothesis, we designed a highly versatile mouse skin model that used vascular endothelial growth factor-expressing cells together with packaging cells producing retroviruses encoding RhoA GTPase mutants. In this animal model, dominant negative N19RhoA selectively impaired assembly of ECs into new blood vessels; and, in contrast, active V14RhoA stimulated ECs to form blood vessels with functional lumens. In vitro, dominant negative N19RhoA reduced EC actin stress fibers and prevented ECs from contracting and reorganizing into precapillary cords within collagen gels. In contrast, active V14RhoA promoted EC stress fiber formation, contractility, and organization into cords. Neither N19RhoA nor V14RhoA significantly affected EC proliferation or migration in vitro; and, similarly, neither mutant significantly affected EC density during angiogenesis in vivo. Thus, these studies identify a critical and selective role for Rho activity in regulating EC assembly into new blood vessels, and they identify both negative and positive manipulation of Rho activity, respectively, as strategies for suppressing or promoting the organizational stages of neovascularization.

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Section: Resultssupporting

confidence: 81%

Rho activity critically and selectively regulates endothelial cell organization during angiogenesis

Hoang

Whelan

Senger

2004

Proc. Natl. Acad. Sci. U.S.A.

179

187

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“…Different signaling pathways are activated by VEGF in order to stimulate endothelial cell migration. Focal adhesion kinase, its substrate paxillin, and the Rho family of GTPases are involved in focal adhesion turnover and stress fiber formation (10,30,31); phosphatidylinositol 3-kinase, ROCK (Rho-associated coiled-coil-containing protein kinase), p38 MAPK, MAP-KAPK-2, and LIMK (LIM domain kinase 1) are involved in actin FIGURE 2. Filamin B is essential for VEGF-induced in vitro angiogenesis and endothelial cell migration.…”

Section: Resultsmentioning

confidence: 99%

Filamin B Plays a Key Role in Vascular Endothelial Growth Factor-induced Endothelial Cell Motility through Its Interaction with Rac-1 and Vav-2

Valle-Pérez

Martínez

Lacasa-Salavert

et al. 2010

Journal of Biological Chemistry

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“…Previous work has shown that VEGF stimulates HUVEC migration [4,5,36]. Since our findings suggested that Vav2 specifically activates Rac1 during VEGF signaling, we investigated whether Vav2 was required for the migration of HUVECs and HMVEC-d towards VEGF.…”

Section: Vav2 Is Necessary For Vegf-induced Endothelial Cell Migrationmentioning

confidence: 92%

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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Rho Family GTPases Regulate VEGF-Stimulated Endothelial Cell Motility

Cited by 128 publications

References 64 publications

Rho activity critically and selectively regulates endothelial cell organization during angiogenesis

Rho activity critically and selectively regulates endothelial cell organization during angiogenesis

Filamin B Plays a Key Role in Vascular Endothelial Growth Factor-induced Endothelial Cell Motility through Its Interaction with Rac-1 and Vav-2

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

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