scholarly journals Endothelial Wnt/β-catenin signaling inhibits glioma angiogenesis and normalizes tumor blood vessels by inducing PDGF-B expression

2012 ◽  
Vol 209 (9) ◽  
pp. 1611-1627 ◽  
Author(s):  
Marco Reis ◽  
Cathrin J. Czupalla ◽  
Nicole Ziegler ◽  
Kavi Devraj ◽  
Jenny Zinke ◽  
...  
Keyword(s):  
Cell Attachment ◽  
Stalk Cell ◽  
Vascular Density ◽  
Mural Cell ◽  
Cell Recruitment ◽  
Vascular Phenotype ◽  
Inhibition Of Angiogenesis ◽  
The Central Nervous System ◽  
Opposing Effects ◽  
Wnt1 Expression

Endothelial Wnt/β-catenin signaling is necessary for angiogenesis of the central nervous system and blood–brain barrier (BBB) differentiation, but its relevance for glioma vascularization is unknown. In this study, we show that doxycycline-dependent Wnt1 expression in subcutaneous and intracranial mouse glioma models induced endothelial Wnt/β-catenin signaling and led to diminished tumor growth, reduced vascular density, and normalized vessels with increased mural cell attachment. These findings were corroborated in GL261 glioma cells intracranially transplanted in mice expressing dominant-active β-catenin specifically in the endothelium. Enforced endothelial β-catenin signaling restored BBB characteristics, whereas inhibition by Dkk1 (Dickkopf-1) had opposing effects. By overactivating the Wnt pathway, we induced the Wnt/β-catenin–Dll4/Notch signaling cascade in tumor endothelia, blocking an angiogenic and favoring a quiescent vascular phenotype, indicated by induction of stalk cell genes. We show that β-catenin transcriptional activity directly regulated endothelial expression of platelet-derived growth factor B (PDGF-B), leading to mural cell recruitment thereby contributing to vascular quiescence and barrier function. We propose that reinforced Wnt/β-catenin signaling leads to inhibition of angiogenesis with normalized and less permeable vessels, which might prove to be a valuable therapeutic target for antiangiogenic and edema glioma therapy.

scholarly journals Complement facilitates developmental microglial pruning of astrocyte and vascular networks

2022 ◽  
Author(s):  
Gopalan Gnanaguru ◽  
Steven J Tabor ◽  
Kentaro Yuda ◽  
Ryo Mukai ◽  
Jörg Köhl ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Immune Cell ◽  
Vascular Density ◽  
Vascular Networks ◽  
Vascular Patterning ◽  
Vascular Growth ◽  
Vascular Bed ◽  
Retinal Microglia ◽  
The Central Nervous System

Microglia, the resident immune cell of the central nervous system, play a pivotal role in facilitating neurovascular development through mechanisms that are not fully understood. This current work resolves a previously unknown role for microglia in facilitating the developmental pruning of the astrocytic template resulting in a spatially organized retinal vascular bed. Mechanistically, our study identified that local microglial expression of complement (C)3 and C3aR is necessary for the regulation of astrocyte patterning and vascular growth during retinal development. Ablation of retinal microglia, loss of C3 or C3aR reduced developmental pruning and clearance of astrocytic bodies leading to increased astrocyte density leading to altered vascular patterning during retinal vascular development. This data demonstrates that C3/C3aR signaling is an important checkpoint required for the finetuning of vascular density during neuroretinal development.

scholarly journals DCE-MRI for Detection of Acute Myeloid Leukemia Derived Bone Marrow Vascular Dysfunction

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 29-29
Author(s):  
Ana Da Silva Gomes ◽  
Bernard Siow ◽  
Diana Passaro ◽  
Dominique Bonnet
Keyword(s):  
Bone Marrow ◽  
Vascular Permeability ◽  
Vascular Function ◽  
Myeloid Leukemia ◽  
Disease Burden ◽  
Vascular Dysfunction ◽  
Vascular Density ◽  
Dce Mri ◽  
Vascular Phenotype ◽  
Acute Myeloid

Acute Myeloid Leukemia (AML) is the most common acute leukemia in adults. While the clinical presentation is quite uniform, it is a highly heterogeneous disease at the genetic level. Using intravital two-photon microscopy in AML xenograft models, we have previously showed that AML patient-derived samples induced a common pathologic bone marrow (BM) vascular phenotype. To understand the translational potential of our findings we have optimized dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) for the assessment of BM vascular dysfunction. We quantified non-model based parameters from DCE-MRI scans: Contrast Enhancement (CE); Wash-in Rate (WiR); and Wash-out Rate (WoR). CE reflects tissue vascular density and is a measurement of the proportion of fully functional vessels per pixel area, WIR reflects blood flow and tissue perfusion, and WoR reflects vascular permeability and tissue clearance capacity. We first measured DCE parameters in control mice. We observed no gender-related differences in BM DCE parameters, while we found significant age-related changes. As mice age, BM vascular density decreases together with increased vascular permeability and reduced tissue clearance capacity. When compared to age- matched controls, mice injected with AML cell lines showed decreased vascular density, decreased blood inflow, increased vascular permeability and reduced tissue clearance capacity. There was a progressive decline in BM vascular function as the disease burden increased, particularly in WiR and WoR parameters, with even low levels of leukemia significantly altering BM vascular function. When analyzing mice injected with AML patient samples, changes in BM vascular function were more dependent on the AML sample than on the engraftment. Low disease burden did not significantly change DCE vascular parameters. At high disease burden, patient-derived xenografts show different degrees of vascular disruption, spanning from global altered DCE parameters to milder phenotypes. Upon AraC treatment, altered vascular parameters remained unchanged in most of the cases, suggesting inability to fully rescue BM vascular function. In conclusion, we showed that DCE-MRI is able to detect consistent changes associated with BM vasculature induced by aging and leukemia. Despite the heterogeneous nature of the disease, our method captures different degrees of vascular alterations, with WIR having the highest diagnostic potential. Our results further suggest that the detection of a pathologic vascular phenotype in the BM of AML patients could be of use in the clinical scenario. Disclosures No relevant conflicts of interest to declare.

scholarly journals Semaphorin SEMA3F and VEGF Have Opposing Effects on Cell Attachment and Spreading

Neoplasia ◽  
2003 ◽  
Vol 5 (1) ◽  
pp. 83-92 ◽  
Author(s):  
Patrick Nasarre ◽  
Bruno Constantin ◽  
Lydie Rouhaud ◽  
Thomas Harnois ◽  
Guy Raymond ◽  
...  
Keyword(s):  
Cell Attachment ◽  
Opposing Effects

scholarly journals Cilia Control Vascular Mural Cell Recruitment in Vertebrates

Cell Reports ◽  
2017 ◽  
Vol 18 (4) ◽  
pp. 1033-1047 ◽  
Author(s):  
Xiaowen Chen ◽  
Dafne Gays ◽  
Carlo Milia ◽  
Massimo M. Santoro
Keyword(s):  
Mural Cell ◽  
Cell Recruitment

scholarly journals Intracerebral injection of proinflammatory cytokines or leukocyte chemotaxins induces minimal myelomonocytic cell recruitment to the parenchyma of the central nervous system.

1992 ◽  
Vol 176 (1) ◽  
pp. 255-259 ◽  
Author(s):  
P B Andersson ◽  
V H Perry ◽  
S Gordon
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Leukocyte Adhesion ◽  
Platelet Activating Factor ◽  
Intracerebral Injection ◽  
Necrosis Factor Alpha ◽  
Cell Recruitment ◽  
The Central Nervous System ◽  
Factor Alpha ◽  
Necrosis Factor

Neither excitotoxic neurodegeneration nor lipopolysaccharide induces an acute myelomonocytic exudate in the murine central nervous system (CNS) parenchyma (Andersson, P.-B., V. H. Perry, and S. Gordon. 1991. Neuroscience, 42:201; Andersson, P.-B., V. H. Perry, and S. Gordon. 1992. Neuroscience 48:169). In this study formyl-methionyl-leucyl-phenylalanine, platelet-activating factor, interleukin 8 (IL-8), IL-1, or tumor necrosis factor alpha were injected into the hippocampus to assess whether these leukocyte chemotaxins and known mediators of recruitment could bypass this block. They induced morphologic activation of microglia and widespread leukocyte margination but little or no cell exudation into the CNS parenchyma. By contrast, there was acute myelomonocytic cell recruitment to the choroid plexus, meninges, and ventricular system, comparable to that in the skin after subcutaneous injection. The normal CNS parenchyma appears to be a tissue unique in its resistance to leukocyte diapedesis, which is shown here to be at a step beyond chemotactic cytokine secretion or induction of leukocyte adhesion to cerebral endothelium.

scholarly journals Analysis of Mural Cell Recruitment to Tumor Vessels

Circulation ◽  
2002 ◽  
Vol 105 (1) ◽  
pp. 112-117 ◽  
Author(s):  
Alexandra Abramsson ◽  
Örjan Berlin ◽  
Hayk Papayan ◽  
Denise Paulin ◽  
Moshe Shani ◽  
...  
Keyword(s):  
Mural Cell ◽  
Tumor Vessels ◽  
Cell Recruitment

scholarly journals Inhibition of Cyclooxygenase-2 Disrupts Tumor Vascular Mural Cell Recruitment and Survival Signaling

2006 ◽  
Vol 66 (8) ◽  
pp. 4378-4384 ◽  
Author(s):  
Alice Lee ◽  
Jason Frischer ◽  
Anna Serur ◽  
Jianzhong Huang ◽  
Jae-O Bae ◽  
...  
Keyword(s):  
Cyclooxygenase 2 ◽  
Mural Cell ◽  
Cell Recruitment ◽  
Survival Signaling
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