Placental Growth Factor, a Member of the VEGF Family, Contributes to the Development of Choroidal Neovascularization

Rakic, Jean-Marie; Lambert, Vincent; Devy, Laetitia; Luttun, Aernout; Carmeliet, Peter; Claes, C; Nguyen, Laurent; Foidart, Jean‐Michel; Noël, Agnès; Munaut, Carine

doi:10.1167/iovs.02-1092

Cited by 287 publications

(218 citation statements)

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“…It has become increasingly evident that no single anti-angiogenic agent (including angiostatin and endostatin) used as monotherapy in preclinical models is able to reduce tumor burden once tumors have reached 100 mm (36). It was shown that the absence of placental growth factor, uPA, or tissue plasminogen activator significantly decreased the development of experimental choroidal neovascularization compared with wild type or uPAR-deficient mice (37). This effect was suggested to be partly due to a modulation of matrix metalloproteinase activity.…”

Section: Figmentioning

confidence: 99%

Specific Interference of Urokinase-type Plasminogen Activator Receptor and Matrix Metalloproteinase-9 Gene Expression Induced by Double-stranded RNA Results in Decreased Invasion, Tumor Growth, and Angiogenesis in Gliomas

Lakka¹,

Gondi²,

Dinh³

et al. 2005

Journal of Biological Chemistry

124

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We have previously demonstrated the effectiveness of adenovirus-mediated expression of antisense urokinase-type plasminogen activator receptor (uPAR) and matrix metalloproteinase-9 (MMP-9) in inhibiting tumor invasion in vitro and ex vivo. However, the therapeutic effect of the adenovirus-mediated antisense approach was shown to be transient and required potentially toxic, high viral doses. In contrast, RNA interference (RNAi)-mediated gene targeting may be superior to the traditional antisense approach, because the target mRNA is completely degraded and the molar ratio of siRNA required to degrade the target mRNA is very low. Here, we have examined the siRNA-mediated target RNA degradation of uPAR and MMP-9 in human glioma cell lines. Using RNAi directed toward uPAR and MMP-9, we achieved specific inhibition of uPAR and MMP-9. This bicistronic construct (pUM) inhibited the formation of capillary-like structures in both in vitro and in vivo models of angiogenesis. We demonstrated that blocking the expression of these genes results in significant inhibition of glioma tumor invasion in Matrigel and spheroid invasion assay models. RNAi for uPAR and MMP-9 inhibited cell proliferation, and significantly reduced the levels of phosphorylated forms of MAPK, ERK, and AKT signaling pathway molecules when compared with parental and empty vector/scrambled vector-transfected SNB19 cells. Furthermore, using RNAi to simultaneously target two proteases resulted in total regression of pre-established intracerebral tumor growth. Our results provide evidence that the use of hairpin siRNA expression vectors for uPAR and MMP-9 may provide an effective tool for cancer therapy. RNA interference (RNAi)1 is a sequence-specific, post-transcriptional gene silencing mechanism, which is triggered by double-stranded RNA and causes the degradation of mRNA homologous in sequence to the double-stranded RNA (1-3). This is an ancient and ubiquitous antiviral system used by organisms to maintain the integrity of the genome, to defend cells against viral infection, and to regulate expression of cellular genes (4). RNAi depends upon the formation of doublestrand RNA (double-stranded RNA) whose antisense strand is complementary to the transcript of a targeted gene. Recently, it has been shown that sequence-specific inhibition RNAi can also be induced in mammalian cells (4, 5). In one implementation of RNAi, selective degradation of target mRNAs in mammalian cells is achieved by transfection with double-stranded, short interfering RNAs (siRNAs), leading to rapid and efficient degradation of the target (4). These siRNAs were shown to avoid the well documented nonspecific effects triggered by longer double-stranded RNAs in mammalian cells.Glioblastoma multiforme is a highly malignant primary central nervous system neoplasm, which is extremely refractory to therapy. One property that makes glioblastoma resistant to treatment is the tendency of the tumor cells to invade normal brain tissue (6). Invasiveness is thus considered to be a major determinant of ...

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Section: Figmentioning

confidence: 99%

Specific Interference of Urokinase-type Plasminogen Activator Receptor and Matrix Metalloproteinase-9 Gene Expression Induced by Double-stranded RNA Results in Decreased Invasion, Tumor Growth, and Angiogenesis in Gliomas

Lakka¹,

Gondi²,

Dinh³

et al. 2005

Journal of Biological Chemistry

124

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“…The cDNAs were amplified in a 50-μl reaction volume containing 20 mmol/l Tris-HCl (pH 8.4), 50 mmol/l potassium chloride, 1.5 mmol/l magnesium chloride, 0.2 mmol/l of each of the dNTPs and 0.5 μmol/l of each appropriate primer: GGCGATGAGAATCTGCACTGT-3′ (forward), 5′-CA CCTTTCCGGCTTCATCTTC-3′ (reverse) for PLGF [17]; 5′-CAAGTGGCCAGAGGCATGGAGTT-3′ (forward), 5′-GATGTAGTCTTTACCATCCTGTTG-3′ (reverse) for VEGFR-1 [18]; 5′-GAGGGCCTCTCATGGTGATTGT-3′ (forward), 5′-TGCCAGCAGTCCAGCATGGTCTG-3′ (reverse) for VEGFR-2 [18]; and 5′-AGGAGAAGCTTGC TACGTC-3′ (forward), 5′-AGGGGCCGGACTCGTCATAC-3′ (reverse) for β-actin, and 2 U Taq polymerase (Invitrogen).…”

Section: Methodsmentioning

confidence: 99%

Placental growth factor-1 and epithelial haemato–retinal barrier breakdown: potential implication in the pathogenesis of diabetic retinopathy

et al. 2006

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Aims/hypothesis Disruption of the retinal pigment epithelial (RPE) barrier contributes to sub-retinal fluid and retinal oedema as observed in diabetic retinopathy. High placental growth factor (PLGF) vitreous levels have been found in diabetic patients. This work aimed to elucidate the influence of PLGF-1 on a human RPE cell line (ARPE-19) barrier in vitro and on normal rat eyes in vivo. Methods ARPE-19 permeability was measured using transepithelial resistance and inulin flux under stimulation of PLGF-1, vascular endothelial growth factor (VEGF)-E and VEGF165. Using RT-PCR, we evaluated the effect of hypoxic conditions or insulin on transepithelial resistance and on PLGF-1 and VEGF receptors. The involvement of mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK, also known as EPHB2) signalling pathways under PLGF-1 stimulation was evaluated by western blot analysis and specific inhibitors. The effect of PLGF-1 on the external haemato-retinal barrier was evaluated after intravitreous injection of PLGF-1 in the rat eye; evaluation was by semi-thin analysis and zonula occludens-1 immunolocalisation on flat-mounted RPE. Results In vitro, PLGF-1 induced a reversible decrease of transepithelial resistance and enhanced tritiated inulin flux. These effects were specifically abolished by an antisense oligonucleotide directed at VEGF receptor 1. Exposure of ARPE-19 cells to hypoxic conditions or to insulin induced an upregulation of PLGF-1 expression along with increased transcellular permeability. The PLGF-1-induced RPE cell permeability involved the MEK signalling pathway. Injection of PLGF-1 into the rat eye vitreous induced an opening of the RPE tight junctions with subsequent sub-retinal fluid accumulation, retinal oedema and cytoplasmic translocation of junction proteins. Conclusions/interpretation Our results indicate that PLGF-1 may be a potential regulation target for the control of diabetic retinal and macular oedema.

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“…A possible implication of these findings is that PlGF blockade might inhibit disease processes more selectively than physiological homeostasis and thus evoke fewer side effects. We summarize below the findings on PlGF's (Foidart et al 2009;Furuya et al 2011) Heart PlGF-induced revascularization of ischemic myocardium and vessel enlargement in remote myocardium preserve cardiac performance following infarction (Luttun et al 2002;Kolakowski et al 2006;Roncal et al 2008) Knockout: impaired angiogenesis and inflammation in infarct border (Carmeliet et al 2001) Knockout: Normal exercise induces angiogenesis (Gigante et al 2004) Skeletal muscle PlGF protein or gene delivery: enhances angiogenesis, collateral growth, and blood flow in ischemic limb (Luttun et al 2002;Pipp et al 2003;Babiak et al 2004); restores microcirculation in aged dystrophic muscle (Gargioli et al 2008) Knockout: impaired collateral growth in ischemic limb (Carmeliet et al 2001;Scholz et al 2003;Gigante et al 2006) Knockout: normal exercise-induced angiogenesis (Gigante et al 2004) Eye PlGF prevents vessel obliteration in hyperoxia without including neovascularization (Shih et al 2003) Local ocular PlGF protein or gene transfer causes hematoretinal barrier breakdown and edema (Miyamoto et al 2007;Kowalczuk et al 2011) Knockout or aPlGF: impaired choroidal neovascularization (Carmeliet et al 2001;Rakic et al 2003;Van de Veire et al 2010) Knockout or aPlGF does not impair retinal vascularization during development (Carmeliet et al 2001;Feeney et al 2003 (Carmeliet et al 2001;Scholz et al 2003;Gigante et al 2006) (Eriksson et al 2002;Xu et al 2006;Schomber et al 2007;Tarallo et al 2010) PlGF educates CD34 þ progenitors to proangiogenic CD11b þ myelomonocytes in breast cancer (Laurent et al 2011...…”

Section: Plgf a Disease-modifying Candidatementioning

confidence: 99%

“…PlGF is elevated in human AMD and mouse models of laser-induced CNV (Rakic et al 2003;Huang et al 2011), whereas PlGF gene deficiency in mice reduces experimental CNV (Rakic et al 2003). Current treatment of CNV in human AMD by VEGF blockade offers visual improvement but requires intravitreal injection and can increase the risk of stroke, ischemic heart disease, and adverse ocular events (Mitchell et al 2010).…”

Section: Diseases With Improved Outcome Following Plgf Blockade Oculamentioning

confidence: 99%

PlGF: A Multitasking Cytokine with Disease-Restricted Activity

Dewerchin¹,

Carmeliet²

2012

Cold Spring Harbor Perspectives in Medicine

194

176

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Placental Growth Factor, a Member of the VEGF Family, Contributes to the Development of Choroidal Neovascularization

Abstract: These observations demonstrate the participation of PlGF in experimental CNV. They identify therefore PlGF as an additional promising target for ocular antiangiogenic strategies.

Cited by 287 publications

References 32 publications

Specific Interference of Urokinase-type Plasminogen Activator Receptor and Matrix Metalloproteinase-9 Gene Expression Induced by Double-stranded RNA Results in Decreased Invasion, Tumor Growth, and Angiogenesis in Gliomas

Specific Interference of Urokinase-type Plasminogen Activator Receptor and Matrix Metalloproteinase-9 Gene Expression Induced by Double-stranded RNA Results in Decreased Invasion, Tumor Growth, and Angiogenesis in Gliomas

Placental growth factor-1 and epithelial haemato–retinal barrier breakdown: potential implication in the pathogenesis of diabetic retinopathy

PlGF: A Multitasking Cytokine with Disease-Restricted Activity

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