Overexpression of Notch1 Ectodomain in Myeloid Cells Induces Vascular Malformations through a Paracrine Pathway

Li, Xiujie; Calvo, Ézéquiel; Cool, Marc; Chrobák, Pavel; Kay, Denis G.; Jolicoeur, Paul

doi:10.2353/ajpath.2007.060351

Cited by 4 publications

(3 citation statements)

References 73 publications

(79 reference statements)

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“…The large vessels under the liver capsule of adult A10⌬EC mice are consistent with a defect in Notch signaling since they resemble those described in transgenic mice overexpressing the Notch1 extracellular domain, 37 which is likely to interfere with Notch signaling in a dominant negative manner. However, unlike the abnormal vessels throughout the liver that were reported by Li et al, the enlarged vessels in A10⌬EC mice were confined to the subcapsular region, and were not seen deeper within the parenchyma.…”

Section: Discussionmentioning

confidence: 67%

Deletion of Adam10 in endothelial cells leads to defects in organ-specific vascular structures

Glomski

Monette²,

Manova

et al. 2011

Blood

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Section: Discussionmentioning

confidence: 67%

Deletion of Adam10 in endothelial cells leads to defects in organ-specific vascular structures

Glomski

Monette²,

Manova

et al. 2011

Blood

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“…To determine vessel integrity, Evans blue (EB; Sigma-Aldrich) was injected i.p. at a dose of 20 l/10 g body weight based on a previous study (27). In brief, rats were perfused with 0.5% formaldehyde after the EB injection.…”

Section: Methodsmentioning

confidence: 99%

“…Total RNA was isolated from tissues using Trizol (Invitrogen) and 1 g RNA was added to real-time PCRs, as described previously (27). Quantitative real-time PCR amplification was performed in triplicate with cDNA and primers in combination with SYBR green (SYBR green 2ϫ mix; Atila Biosystems, Palo Alto, CA) on a MyiQ single-color real-time PCR machine (Bio-Rad).…”

Section: Methodsmentioning

confidence: 99%

Neurodegeneration Induced by PVC-211 Murine Leukemia Virus Is Associated with Increased Levels of Vascular Endothelial Growth Factor and Macrophage Inflammatory Protein 1α and Is Inhibited by Blocking Activation of Microglia

Hanson

Cmarik

et al. 2009

J Virol

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PVC-211 murine leukemia virus (MuLV) is a neuropathogenic retrovirus that has undergone genetic changes from its nonneuropathogenic parent, Friend MuLV, that allow it to efficiently infect rat brain capillary endothelial cells (BCEC). To clarify the mechanism by which PVC-211 MuLV expression in BCEC induces neurological disease, we examined virus-infected rats at various times during neurological disease progression for vascular and inflammatory changes. As early as 2 weeks after virus infection and before any marked appearance of spongiform neurodegeneration, we detected vessel leakage and an increase in size and number of vessels in the areas of the brain that eventually become diseased. Consistent with these findings, the amount of vascular endothelial growth factor (VEGF) increased in the brain as early as 1 to 2 weeks postinfection. Also detected at this early disease stage was an increased level of macrophage inflammatory protein 1␣ (MIP-1␣), a cytokine involved in recruitment of microglia to the brain. This was followed at 3 weeks postinfection by a marked accumulation of activated microglia in the spongiform areas of the brain accompanied by an increase in tissue plasminogen activator, a product of microglia implicated in neurodegeneration. Pathological observations at the end stage of the disease included loss of neurons, decreased myelination, and mild muscle atrophy. Treatment of PVC-211 MuLV-infected rats with clodronate-containing liposomes, which specifically kill microglia, significantly blocked neurodegeneration. Together, these results suggest that PVC-211 MuLV infection of BCEC results in the production of VEGF and MIP-1␣, leading to the vascular changes and microglial activation necessary to cause neurodegeneration.

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Blei¹

2007

Lymphatic Research and Biology

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E-pub ahead of print]. AbstractThe discovery of marker proteins of human blood (BECs) and lymphatic endothelial cells (LECs) has allowed the isolation of these cells. So far, efforts to unravel their transcriptional and functional programs made use of cultured cells only. Hence, it is unknown to which extent previously identified LEC-and BEC-specific programs are representative of the in vivo situation. Here, we define the human BEC-and LEC-specific in vivo transcriptomes by comparative genome-wide expression profiling of freshly isolated cutaneous EC subsets and of non-EC skin cells (fibroblasts, mast cells, dendritic cells, epithelial cells). Interestingly, the expression of most of the newly identified EC subset-discriminating genes depends strictly on the in vivo tissue environment as revealed by comparative analyses of freshly isolated and cultured EC subsets. The identified environment-dependent, EC subset-restricted gene expression regulates lineage fidelity, fluid exchange, and MHC class II-dependent antigen presentation. As an example, for a BEC-restricted in vivo function, we show that non-activated BECs in situ, but not in vitro, assemble and display MHC class II protein complexes loaded with self peptides. Thus, our data demonstrate the key importance of using precisely defined native ECs for the global identification of in vivo relevant cell functions.This study compares, via FACS, rtPCR and microarray analyses, the characteristics of freshly isolated versus cultured blood vessel and lymphatic endothelial cells. Other skin cell types were studied to identify the distinctiveness of the endothelial cell subtypes. They found striking differences in gene expression between the freshly harvested cells and those that had undergone several passages in culture, postulating environment-dependent processes modulating protein expression and function.Blood vessel endothelial cells maintained expression of CD-146 and HOXD10 and lymphatic endothelial cells continued to express Podoplanin, LYVE-, PROX-1 and FOXC2 (thus these markers that differentiate the two cell types in vitro). A surprising finding was constitutive MHC class II-related protein expression by the normal vessel endothelial cells was lost when the cells were cultured in vitro. Further studies investigated the mechanism of MHC class II and T cell function. The authors conclude that further research may facilitate therapeutic manipulation of these cell types.

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Overexpression of Notch1 Ectodomain in Myeloid Cells Induces Vascular Malformations through a Paracrine Pathway

Abstract: We previously reported that truncation of Notch1 (N1) by provirus insertion leads to overexpression of both the intracellular (N1 IC ) and the extracellular (N1 EC ) domains. We produced transgenic (Tg) mice expressing N1 EC

Cited by 4 publications

References 73 publications

Deletion of Adam10 in endothelial cells leads to defects in organ-specific vascular structures

Deletion of Adam10 in endothelial cells leads to defects in organ-specific vascular structures

Neurodegeneration Induced by PVC-211 Murine Leukemia Virus Is Associated with Increased Levels of Vascular Endothelial Growth Factor and Macrophage Inflammatory Protein 1α and Is Inhibited by Blocking Activation of Microglia

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