Angiogenesis in multiple sclerosis: is it good, bad or an epiphenomenon?

Kirk, S.L; Frank, Joseph A.; Karlik, Stephen J.

doi:10.1016/j.jns.2003.10.016

Cited by 67 publications

(53 citation statements)

References 62 publications

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“…Furthermore, VEGFA and DDR together exhibit a stronger outcome in terms of decreasing CLDN5 and OCLN levels and promoting permeability. Interestingly, our gene expression profiling studies indicate that DDR and VEGFA downregulation of endothelial tight junction proteins represents part of a wider plasticity response, compatible with previous observations suggestive of angiogenesis in lesions in multiple sclerosis and its models (Ludwin and McFarland, 2001;Kirk et al, 2004;Muramatsu et al, 2012). In these BeadArrayß experiments, we found that VEGFA regulates 80 genes, whereas the DDR profile of activity includes 41 genes.…”

Section: Discussionsupporting

confidence: 91%

Astrocytic TYMP and VEGFA drive blood–brain barrier opening in inflammatory central nervous system lesions

Chapouly

Argaw

Horng

et al. 2015

Brain

141

136

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*These authors contributed equally to this work.In inflammatory central nervous system conditions such as multiple sclerosis, breakdown of the blood-brain barrier is a key event in lesion pathogenesis, predisposing to oedema, excitotoxicity, and ingress of plasma proteins and inflammatory cells. Recently, we showed that reactive astrocytes drive blood-brain barrier opening, via production of vascular endothelial growth factor A (VEGFA). Here, we now identify thymidine phosphorylase (TYMP; previously known as endothelial cell growth factor 1, ECGF1) as a second key astrocyte-derived permeability factor, which interacts with VEGFA to induce blood-brain barrier disruption. The two are co-induced NFB1-dependently in human astrocytes by the cytokine interleukin 1 beta (IL1B), and inactivation of Vegfa in vivo potentiates TYMP induction. In human central nervous system microvascular endothelial cells, VEGFA and the TYMP product 2-deoxy-D-ribose cooperatively repress tight junction proteins, driving permeability. Notably, this response represents part of a wider pattern of endothelial plasticity: 2-deoxy-D-ribose and VEGFA produce transcriptional programs encompassing angiogenic and permeability genes, and together regulate a third unique cohort. Functionally, each promotes proliferation and viability, and they cooperatively drive motility and angiogenesis. Importantly, introduction of either into mouse cortex promotes blood-brain barrier breakdown, and together they induce severe barrier disruption. In the multiple sclerosis model experimental autoimmune encephalitis, TYMP and VEGFA co-localize to reactive astrocytes, and correlate with blood-brain barrier permeability. Critically, blockade of either reduces neurologic deficit, blood-brain barrier disruption and pathology, and inhibiting both in combination enhances tissue preservation. Suggesting importance in human disease, TYMP and VEGFA both localize to reactive astrocytes in multiple sclerosis lesion samples. Collectively, these data identify TYMP as an astrocyte-derived permeability factor, and suggest TYMP and VEGFA together promote blood-brain barrier breakdown.

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Section: Discussionsupporting

confidence: 91%

Astrocytic TYMP and VEGFA drive blood–brain barrier opening in inflammatory central nervous system lesions

Chapouly

Argaw

Horng

et al. 2015

Brain

141

136

View full text Add to dashboard Cite

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“…61,62 In an allergic encephalomyelitis model that mimics multiple sclerosis, VEGF-A immunoreactivity increased in parallel with the development of the typical histologic changes characteristic of encephalomyelitis, implicating this angiogenic cytokine in facilitating the development of long-term neural inflammation and eventually demyelination. 63 VEGF-A infusions directly into the neocortex of normal rats increased vascular density progressively over a 7-day period and were accom-panied by an early (Ͻ24 hours) and marked dose-dependent extravasation of IgG and leukocytes. 64 Staining for ED-1 antigen indicated that most of the inflammatory cells were of monocyte/macrophage origin.…”

Section: Angiogenic Cytokines and Inflammationmentioning

confidence: 99%

Innate Immunity and Angiogenesis

Frantz¹,

Vincent²,

Feron³

et al. 2005

Circulation Research

169

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Abstract-Activation of an innate immune response is among the first lines of defense after tissue injury. Restoring blood flow to the site of injured tissue is often a necessary prerequisite for mounting an initial immune response to pathogens and for subsequent initiation of a successful repair of wounded tissue. The multiple links among pathogen recognition and suppression, increased angiogenesis, and tissue repair are the topics of this review, which examines of the roles of antimicrobial peptides, mammalian toll-like receptors (TLRs), inflammatory cytokines, and putative "danger" signals, among other signaling pathways, in triggering, sustaining, and then terminating an angiogenic response.

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“…It is observed at tightly regulated condition in normal physiology during embryogenesis, ovary cycling, and wound healing. However, in pathological conditions such as inflammatory diseases, rheumatoid arthritis and tumor metastasis, a chronic unregulated angiogenic state often helps spreading of the diseases (Kirk, Frank, & Karlik, 2004). Hence, preventing angiogenesis under pathological conditions is promising approach in the prevention of cancer and other angiogenicrelated diseases.…”

Section: Anti-angiogenic Activitymentioning

confidence: 99%