Role of PlGF in the intra- and intermolecular cross talk between the VEGF receptors Flt1 and Flk1

Autiero, Monica; Waltenberger, Johannes; Communi, Didier; Kranz, Andrea; Moons, Lieve; Lambrechts, Diether; Krøll, Jens; Plaisance, Stéphane; Mol, Maria De; Bono, Françoise; Kliche, Stefanie; Fellbrich, Guido; Ballmer-Hofer, Kurt; Maglione, Domenico; Mayr-Beyrle, Ulrike; Dewerchin, Mieke; Dombrowski, Saskia; Stanimirovic, Danica; Hummelen, Paul Van; Dehio, Christoph; Hicklin, Daniel J.; Persico, Graziella; Herbert, Jean‐Marc; Communi, David; Shibuya, Masabumi; Collen, D.; Conway, Edward M.; Carmeliet, Peter

doi:10.1038/nm884

Cited by 682 publications

(610 citation statements)

References 44 publications

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“…It can also form a heterodimer with PlGF, and this stimulates angiogenesis via the VEGFR-1/VEGFR-2 heterodimer (Autiero et al, 2003;Roy et al, 2006); this is consistent with our finding that VEGF/PlGF was present at substantially higher levels in AML patients than in the healthy controls. Loges et al (2005) reported that the AML patients and healthy donors …”

Section: Discussionsupporting

confidence: 92%

Marrow angiogenesis-associated factors as prognostic biomarkers in patients with acute myelogenous leukaemia

Tien

et al. 2007

Br J Cancer

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Bone marrow (BM) neoangiogenesis plays an important role in acute myelogenous leukaemia (AML), and depends on the interplay of members of the vascular endothelial growth factor (VEGF) and angiopoietin (Ang) families. We determined the marrow levels of seven molecules associated with angiogenesis in 52 AML patients before chemotherapy and 20 healthy controls: VEGF-A, VEGF/PlGF, VEGF-C, VEGF-D, Ang-1, Ang-2, and Tie-2. All the molecules were quantified using enzyme-linked immunosorbent assay (ELISA). Comparing to normal controls, the marrow levels of VEGF/PlGF, Ang-2, and Tie-2 were significantly higher, and those of VEGF-C and Ang-1 were significantly lower in the AML patients ( P <0.001). A total of 31 patients were further subjected to survival analysis. Patients with lower Tie-2 (<26 ng ml −1 ) and Ang-2 levels (<4500 pg ml −1 ) displayed a survival advantage ( P =0.037 and 0.042, respectively), same as patients with higher VEGF/PlGF (⩾1 pg ml −1 ) and VEGF-D levels (⩾350 pg ml −1 ) ( P =0.020 and 0.016, respectively). An angio-index ((Ang-2 × Tie-2)/(VEGF/PlGF × VEGF-D)) was established and multivariate Cox regression analysis revealed that patients with higher angio-index values (⩾50) displayed poor prognosis (hazard ratio 5.91, 95% confidence interval 1.99–17.56; P =0.001). The angio-index is closely associated with the clinical outcome of AML patients and may be valuable in disease prognosis.

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Section: Discussionsupporting

confidence: 92%

Marrow angiogenesis-associated factors as prognostic biomarkers in patients with acute myelogenous leukaemia

Tien

et al. 2007

Br J Cancer

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“…In the vascular endothelium, VEGF increases paracellular permeability by the activation of VEGF-R2 receptors (Autiero et al 2003;Gille et al 2001;Shen et al 1999). However, a recent study by Miyamoto and colleagues concluded that the VEGF-R1 receptor subtype mediated VEGF-induced changes in the barrier properties of ARPE-19 cell monolayers (Miyamoto et al 2007).…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, in order to begin to understand how VEGF contributes to the regulation of RPE barrier function, it is essential to understand how individual VEGF receptors effect RPE physiology. In vascular endothelial cells, there is growing evidence that increases in permeability and proliferation are mediated by VEGF-R2 activation, and within the choroid, that these actions can be opposed by VEGF-R1 stimulation (Autiero et al 2003;Gille et al 2001;Nozaki et al 2006;Shen et al 1999). However, a recent study of the RPE concluded that VEGF-R1 receptor activation is responsible for the VEGF-induced increase in epithelial permeability (Miyamoto et al 2007).…”

Section: Introductionmentioning

confidence: 99%

VEGF modulation of retinal pigment epithelium resistance

Ablonczy

Crosson

2007

Experimental Eye Research

127

110

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Fluid accumulation into the subretinal space and the development of macular edema is a common condition in age-related macular degeneration, diabetic retinopathy, and following ocular surgery, or injury. Vascular endothelial growth factor (VEGF) and other cytokines have been implicated in the disruption of retinal pigment epithelium (RPE) barrier function and a reduction in the regulated removal of subretinal fluid; however, the cellular and molecular events linking these agents to the disruption of barrier function have not been established. In the current study, cultures of ARPE-19 and primary porcine retinal pigment epithelium (RPE) cells were utilized to investigate the effects of the VEGF-induced modifications to the barrier properties of the RPE. The barrier function was determined by transepithelial resistance (TER) measurements and morphology of the RPE monolayers. In both ARPE-19 and primary porcine RPE cells the administration of VEGF produced a significant drop in TER, and this response was only observed following apical administration. Maximum reduction in TER was reached 5 hours post VEGF administration. These responses were concentration-dependent with an EC 50 of 502 pg/mL in ARPE-19 cells and 251 pg/mL in primary porcine cells. In both ARPE-19 and primary RPE cells, the response to VEGF was blocked by pretreatment with the relatively selective VEGF-R2 antagonists, SU5416 or ZM323881, or the protein tyrosine kinase inhibitor, genistein. Administration of the relatively selective VEGF-R2 agonist, VEGF-E, also reduced TER in a concentration-dependent manner (EC 50 of 474 pg/mL), while VEGF-R1 agonist, placental growth factor (PlGF), did not significantly alter the TER. Immunolocalization studies demonstrated that confluent monolayers exhibited continuous cell-tocell ZO-1 protein contacts and apical localization of the VEGF-R2 receptors. These data provide evidence that the VEGF-induced breakdown of RPE barrier function is mediated by the activation of apically-oriented VEGF-R2 receptors. Thus, VEGF-mediated increases in RPE permeability are initiated by a rise in intraocular levels of VEGF.

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“…Like most solid tumors, gliomas express and secrete vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) that induces proliferation and migration of neighboring endothelial cells [32][33][34][35][36]. Remodeling of the BBB vasculature by VEGF disrupts the formation of tight junctions, increases vascular permeability (VP), and results in a disordered vasculature characteristic of tumor-induced angiogenesis [34,[37][38][39].…”

Section: Introductionmentioning

confidence: 99%

Reduced Glioma Infiltration in Src-deficient Mice

et al. 2006

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SummaryMalignant brain tumors, such as glioblastoma, are characterized by extensive angiogenesis and permeability of the blood-brain barrier (BBB). The infiltration of glioma cells away from the primary tumor mass is a pathological characteristic of glial tumors. The infiltrating tumor cells represent a significant factor in tumor recurrence following surgical debulking, radiation, and chemotherapy treatments. Vascular endothelial growth factor (VEGF)-mediated vascular permeability (VP) has been associated with the progression of glioma tumor growth and infiltration into surrounding normal brain parenchyma. While VEGF induces a robust VP response in control mice (src +/+ or src +/− ), the VP response is blocked in src −/− mice that demonstrate a 'leakage-resistant phenotype' in the brain. We used the Src-deficient mouse model to determine the role of Src in the maintenance of the BBB following orthotopic implantation and growth of glioma cells in the brain. Although solid tumor growth was the same in control and src −/− mice, the infiltrating component of glioma growth was reduced in src −/− mice. Characterization of the expression and localization of the extracellular matrix (ECM) protein fibrinogen was evaluated to determine the effect of a Src-mediated VP defect in the host compartment. These studies indicate that the reduced VP of host brain blood vessels of src −/− mice mediates a reduction in glioma cell invasion in a mouse brain tumor xenograft model.

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Role of PlGF in the intra- and intermolecular cross talk between the VEGF receptors Flt1 and Flk1

Cited by 682 publications

References 44 publications

Marrow angiogenesis-associated factors as prognostic biomarkers in patients with acute myelogenous leukaemia

Marrow angiogenesis-associated factors as prognostic biomarkers in patients with acute myelogenous leukaemia

VEGF modulation of retinal pigment epithelium resistance

Reduced Glioma Infiltration in Src-deficient Mice

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