VEGF enhances angiogenesis and promotes blood-brain barrier leakage in the ischemic brain

Zhang, Zheng Gang; Zhang, Li; Jiang, Quan; Zhang, Ruilan; Davies, Kenneth; Powers, Cecylia; Bruggen, Nicholas van; Chopp, Michael

doi:10.1172/jci9369

Cited by 1,180 publications

(1,019 citation statements)

References 66 publications

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“…Gliomas express a range of growth factors and cytokines, however VEGF is unique among these growth factors in that it induces VP as well as neovascularization [55][56][57][58]. Intra-cranial administration of recombinant VEGF to mice has been shown to increase VP and result in breakdown of the BBB, however the mechanisms regulating this process remain poorly understood [59][60][61]. Therefore, in this study we have examined Src-deficient mice, which we have previously shown to have a 'leakage-resistant' phenotype in response to VEGF.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

confidence: 99%

Reduced Glioma Infiltration in Src-deficient Mice

et al. 2006

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“…Concentrations of erythropoietin and other haematological values associated with increased erythropoiesis (including haematocrit, haemoglobin concentration and proportion of haemoglobin F) were seen to be higher in cord blood samples including those of pregnancies associated with maternal diabetes mellitus [38]. VEGF can influence the molecular residency and phosphorylation status of junctional adhesion molecules [14,15], enhancing angiogenesis and promoting vascular leakage [39,40,41], whilst it has been shown that the complexing of VEGF receptor-2 with VE-cadherin, β-catenin and PI3-kinase is required for the endothelial survival function of VEGF [8,9]. In our diabetic group over 70% of vessels showed phospho-tyrosine immunoreactivity at paracellular clefts , suggesting that phosphorylation of cell-cell adhesion molecules and other lateral membrane receptors is a key feature in the Type 1 diabetic placenta.…”

Section: Discussionmentioning

confidence: 99%

Vascular endothelial cadherin and �-catenin in human fetoplacental vessels of pregnancies complicated by Type 1 diabetes: associations with angiogenesis and perturbed barrier function

et al. 2004

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Aims/hypothesis. Increased angiogenesis of fetoplacental vessels is a feature of pregnancies complicated by Type 1 diabetes mellitus, but the underlying molecular mechanisms are unknown. This investigation tests whether the diabetic maternal environment alters the phenotypic expression of placental vascular endothelial cadherin and β-catenin, which have been implicated as key molecules in barrier formation and angiogenesis in the endothelium. Methods. Term placental microvessels from normal pregnancies (n=8) and from those complicated by Type 1 diabetes (n=8) were perfused with 76-M r dextran tracers (1 mg/ml) and subjected to immunocytochemistry, immunoblotting and microscopy. Junctional integrity, localisation and phosphorylation were investigated along with total protein levels of vascular endothelial cadherin, β-catenin and vascular endothelial growth factor. Stereological sampling and estimation tools were used to quantify aspects of angiogenesis and endothelial proliferation. Results. In the Type 1 diabetic placentae, junctional localisations of vascular endothelial cadherin and β-catenin altered significantly, with more than 50% of microvessels showing complete loss of immunoreactivity and with no overall loss of total protein. Tracer leakage was associated with these vessels. There was a two-to three-fold increase in vessels showing junctional phospho-tyrosine immunoreactivity and hyperphosphorylated β-catenin. Vascular endothelial growth factor levels were higher in these placentae. A fourfold increase in endothelial proliferation was observed, along with an increase in total length of capillaries without any change in luminal diameter. Conclusions/interpretation. Molecular perturbations of vascular endothelial cadherin and β-catenin occur in fetoplacental vessels of pregnancies complicated by Type 1 diabetes. Phosphorylation and loss of these molecules from the adherens junctional domains may be influenced in part by the elevated levels of vascular endothelial growth factor in the placenta. Perturbations of the junctional proteins may explain the observed breach in barrier integrity and may contribute to the mechanisms that drive proliferation and increases in capillary length.

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“…109,110 However, early postischemic (1 hour) administration of recombinant human VEGF165 (rh-VEGF165) to ischemic rats increased BBB leakage and infarction volume in the ischemic brain. 111 In contrast, late (48 hours) administration of rhVEGF165 to ischemic rats enhanced angiogenesis in the ischemic penumbra and significantly improved neurological recovery, 111 and combination ANG1-VEGF treatment decreased BBB leakage and promoted angiogenesis. 112 VEGF stimulates angiogenesis and neurogenesis, and improves functional outcome after stroke, through multiple mechanisms.…”

Section: Vascular Endothelial Growth Factormentioning

confidence: 99%

Neurorestorative treatment of stroke: Cell and pharmacological approaches

Chen

Chopp

2006

NeuroRX

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154

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Summary:There is a compelling need to develop cell and pharmacological therapeutic approaches to be administered beyond the hyperacute phase of stroke. These therapies capitalize on the capacity of the brain for neuroregeneration and neuroplasticity and are designed to reduce neurological deficits after stroke. This review provides an update of bone marrowderived mesenchymal stem cells (MSCs) and select pharmacological agents in clinical use for other indications that promote the recovery process in the subacute and chronic phases after stroke. Among these agents are 3-hydroxy-3-methylglutarylcoenzyme A reductase inhibitors (statins), erythropoietin (EPO), and phosphodiesterase type 5 (PDE-5) inhibitors and nitric oxide (NO) donors. Both the MSCs and the pharmacologic agents potentiate brain plasticity and neurobehavioral recovery after stroke.

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VEGF enhances angiogenesis and promotes blood-brain barrier leakage in the ischemic brain

Cited by 1,180 publications

References 66 publications

Reduced Glioma Infiltration in Src-deficient Mice

Reduced Glioma Infiltration in Src-deficient Mice

Vascular endothelial cadherin and �-catenin in human fetoplacental vessels of pregnancies complicated by Type 1 diabetes: associations with angiogenesis and perturbed barrier function

Neurorestorative treatment of stroke: Cell and pharmacological approaches

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