Aspirin-triggered Lipoxin A4 inhibition of VEGF-induced endothelial cell migration involves actin polymerization and focal adhesion assembly

Cezar-de-Mello, P F T; Nascimento-Silva, Vany; Villela, Christina Gaspar; Fierro, Iolanda M.

doi:10.1038/sj.onc.1209002

Cited by 84 publications

(61 citation statements)

References 41 publications

(39 reference statements)

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“…It has been shown that ATL-1 inhibits the VEGF-induced formation of actin stress fibers, but ATL-1 alone does not have the same effect (30). On the contrary, in our experimental conditions, native LXA 4 causes a profound change in actin rearrangement.…”

Section: Lxa 4 Stimulates Actin Rearrangement and Inhibits Vegf-and Lcontrasting

confidence: 42%

“…Work by Fierro and colleagues has shown the stable synthetic analog of ATL, 15-epi-16-(para-fluoro)-phenoxy-LXA 4 (ATL-1), inhibits VEGF-and LTD 4 -stimulated angiogenesis in vitro and in vivo (29 -31). Additionally, ATL-1 has been shown to regulate the proteolytic activity necessary to digest basement membrane (30) and to modulate endothelial cell migration (31), key events in the angiogenic process (32).…”

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confidence: 99%

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Lipoxin A4: Anti-Inflammatory and Anti-Angiogenic Impact on Endothelial Cells

Baker

O'Meara²,

Scannell³

et al. 2009

The Journal of Immunology

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Lipoxins (LX) are a class of eicosanoid that possesses a wide spectrum of antiinflammatory and proresolution bioactions. Here we have investigated the impact of the endogenously produced eicosanoid LXA4 on endothelial cell inflammatory, proliferative, and antigenic responses. Using HUVECs we demonstrate that LXA4 inhibits vascular endothelial growth factor (VEGF)-stimulated inflammatory responses including IL-6, TNF-α, IFN-γ and IL-8 secretion, as well as endothelial ICAM-1 expression. Interestingly, LXA4 up-regulated IL-10 production from HUVECs. Consistent with these antiinflammatory and proresolution responses to LXA4, we demonstrate that LXA4 inhibited leukotriene D4 and VEGF-stimulated proliferation and angiogenesis as determined by tube formation of HUVECs. We have explored the underlying molecular mechanisms and demonstrate that LXA4 pretreatment is associated with the decrease of VEGF-stimulated VEGF receptor 2 (KDR/FLK-1) phosphorylation and downstream signaling events including activation of phospholipase C-γ, ERK1/2, and Akt.

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Section: Lxa 4 Stimulates Actin Rearrangement and Inhibits Vegf-and Lcontrasting

confidence: 42%

mentioning

confidence: 99%

Lipoxin A4: Anti-Inflammatory and Anti-Angiogenic Impact on Endothelial Cells

Baker

O'Meara²,

Scannell³

et al. 2009

The Journal of Immunology

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“…41 Also, VEGF activates the p38 MAPK pathway that is required for mitogenic activity in ECs and has been EMAP II interferes with VEGF signaling N Awasthi et al implicated in cell migration. 42,43 In our study, we observed that EMAP II preincubation inhibited VEGF-induced activation of elements of all these downstream signaling pathways, namely Raf, Erk1/2, Akt and p38. This inhibition of phosphorylation of VEGF-induced cytoplasmic signaling proteins likely reflects a functional interference with the VEGF to VEGFR interaction, and represents a mechanism for the known effects of EMAP II on survival, proliferation, differentiation and migration of ECs.…”

Section: Discussionmentioning

confidence: 70%

“…This finding correlates with our observation that EMAP II blocks VEGF-induced activation of p38 MAPK, which has been implicated in EC migration. 42,43 In summary, our study demonstrated that EMAP II interacts with VEGF receptors, which inhibits VEGF receptor activation and causes inhibition of VEGF-induced activation of downstream signaling proteins. We also showed that EMAP II inhibits VEGF-induced ECs proliferation and migration.…”

Section: Discussionmentioning

confidence: 99%

Endothelial monocyte activating polypeptide II interferes with VEGF-induced proangiogenic signaling

Awasthi

Schwarz

Verma

et al. 2009

Laboratory Investigation

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Endothelial monocyte activating polypeptide II (EMAP II) is a proinflammatory cytokine with antiangiogenic properties. EMAP II functions as a potent inhibitor of primary and metastatic tumor growth, has strong inhibitory effects on endothelial cells (ECs), and can reduce intratumoral expression of the angiogenesis inducer vascular endothelial growth factor (VEGF). VEGF influences EC functions such as proliferation, migration, survival and tube formation. Therapeutic strategies that target VEGF have been demonstrated to reduce the tumor growth. We investigated the effects of EMAP II on VEGF-induced angiogenesis signaling. Primary human fetal lung ECs (HFLECs) and human umbilical vein ECs (HUVECs) were grown in E-Stim medium. Protein binding was analyzed using enzyme-linked immunosorbent assay (ELISA). Protein expression was determined by western blot analysis. EC proliferation and migration was determined using WST-1 reagent and transwell membrane, respectively. EMAP II efficiently and dose dependently binds to VEGF receptor 1 (VEGFR1) and VEGF receptor 2 (VEGFR2) as observed by ELISA. B max values for VEGFR1 and VEGFR2 were 0.45 and 0.17, respectively. In addition, EMAP II inhibited binding of VEGF to VEGFR1 and VEGFR2. EMAP II significantly reduced VEGF-induced expression of phosphorylated VEGFR1 (in HFLEC and HUVEC) by 450%, and of phosphorylated VEGFR2 (in HUVEC) by 66%. EMAP II also inhibited downstream VEGF signaling. Although VEGF-induced phosphorylation of Akt, Erk1/2, p38 and Raf 2.8-, 1.5-, 2.2-and 3.6-fold, respectively, EMAP II preincubation blocked this induction in phosphorylation to control levels. VEGF-induced EC proliferation 2.5-fold, and EMAP II pretreatment abrogated this effect. Similarly, VEGF-induced EC migration (2.5-fold) was significantly inhibited by EMAP II. These finding suggest that inhibition of VEGF signaling is one possible antiangiogenic mechanism of EMAP II, which may explain its in vivo antitumor activity and delineate therapeutic strategies to enhance anti-VEGF therapy to inhibit tumor growth.

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“…At the molecular level, both VEGF and mechanical signals are known to regulate common elements such as polymerisation of actin and FAK and PI3K activation (1) (45) (11).…”

Section: Introductionmentioning

confidence: 99%

Mechanical signals modulated vascular endothelial growth factor-A (VEGF-A) alternative splicing in osteoblastic cells through actin polymerisation

Faure

Linossier

Malaval

et al. 2008

Bone

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To cite this version:Céline None of the authors has any conflicts of interest. A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT AbstractSince VEGF-A is involved in mechanically-induced bone gain and because vegf exists under 6 isoforms exerting various biological effects, we studied vegf isoforms expression and VEGF protein production in osteoblastic cells (rat Ros17/2.8 and human osteoblasts) submitted to 4 mechanical regimens. Mechanical regimens (1% stretch deformation)were designed with a fixed number of cycles (450) mRNA expressions of soluble VEGF isoforms (121,165) were specifically expressed under low frequency while matrix-bound VEGF isoforms (206, 189, 165, 145) were specifically expressed under high frequency in human osteoblasts. As F-actin stress fibers formation was significantly increased selectively in high frequencies conditions, we disrupted actin fibers in Ros17/2.8 and found that immobilisation of VEGF was abolished. Conversely, jasplakinolide treatment which increases stress fibers formation was able to mimic high frequency stretch-induced immobilisation of VEGF. Thus, we speculate that the stretchinduced increase in cell tension is responsible for matrix-bound vegf isoform production.Mechanically-induced selection of soluble or matrix-bound VEGF production may modify osteoblast and endothelial c ells crosstalk crucial during osteogenesis and fracture healing.

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Aspirin-triggered Lipoxin A4 inhibition of VEGF-induced endothelial cell migration involves actin polymerization and focal adhesion assembly

Cited by 84 publications

References 41 publications

Lipoxin A4: Anti-Inflammatory and Anti-Angiogenic Impact on Endothelial Cells

Lipoxin A4: Anti-Inflammatory and Anti-Angiogenic Impact on Endothelial Cells

Endothelial monocyte activating polypeptide II interferes with VEGF-induced proangiogenic signaling

Mechanical signals modulated vascular endothelial growth factor-A (VEGF-A) alternative splicing in osteoblastic cells through actin polymerisation

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