Mechanisms of angiogenesis in microbe-regulated inflammatory and neoplastic conditions

Sajib, Sanaullah; Zahra, Fatema Tuz; Lionakis, Michail S.; German, Nadezhda; Mikelis, Constantinos M.

doi:10.1007/s10456-017-9583-4

Cited by 127 publications

(79 citation statements)

References 131 publications

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“…As well as VEGF-A binding its orthosteric ligand binding site, allosteric interactions can occur at topographically distinct regions [ 99 ]. Allosteric homotypic interactions between VEGFR2 monomers at Ig-like D4, D5 and D7 are an additional step necessary for VEGFR2 activation [ 84 , 100 , 101 , 102 , 103 ], as designed ankyrin repeat protein inhibitors (DARPins) can sterically block these interactions and allosterically inhibit VEGFR2 activation [ 103 , 104 ]. Ligand binding leads to a conformational twist throughout the extracellular region of VEGFR2 reorienting distinct Ig-like domains, shown by electron microscopy [ 100 ], small angle X-ray scattering [ 101 ], and the full-length crystal structure of structurally related VEGFR1 [ 88 ].…”

Section: Vegfr2 Signallingmentioning

confidence: 99%

Molecular Pharmacology of VEGF-A Isoforms: Binding and Signalling at VEGFR2

Peach

Mignone

Arruda

et al. 2018

IJMS

366

279

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Vascular endothelial growth factor-A (VEGF-A) is a key mediator of angiogenesis, signalling via the class IV tyrosine kinase receptor family of VEGF Receptors (VEGFRs). Although VEGF-A ligands bind to both VEGFR1 and VEGFR2, they primarily signal via VEGFR2 leading to endothelial cell proliferation, survival, migration and vascular permeability. Distinct VEGF-A isoforms result from alternative splicing of the Vegfa gene at exon 8, resulting in VEGFxxxa or VEGFxxxb isoforms. Alternative splicing events at exons 5–7, in addition to recently identified posttranslational read-through events, produce VEGF-A isoforms that differ in their bioavailability and interaction with the co-receptor Neuropilin-1. This review explores the molecular pharmacology of VEGF-A isoforms at VEGFR2 in respect to ligand binding and downstream signalling. To understand how VEGF-A isoforms have distinct signalling despite similar affinities for VEGFR2, this review re-evaluates the typical classification of these isoforms relative to the prototypical, “pro-angiogenic” VEGF165a. We also examine the molecular mechanisms underpinning the regulation of VEGF-A isoform signalling and the importance of interactions with other membrane and extracellular matrix proteins. As approved therapeutics targeting the VEGF-A/VEGFR signalling axis largely lack long-term efficacy, understanding these isoform-specific mechanisms could aid future drug discovery efforts targeting VEGF receptor pharmacology.

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Section: Vegfr2 Signallingmentioning

confidence: 99%

Molecular Pharmacology of VEGF-A Isoforms: Binding and Signalling at VEGFR2

Peach

Mignone

Arruda

et al. 2018

IJMS

366

279

View full text Add to dashboard Cite

show abstract

“…For studying tumor angiogenesis, different approaches exist. A compilation of the currently used in vivo, ex vivo , and in vitro bioassays has been recently published as a collaborative work of some of the main experts in the angiogenesis field ( 15 ). Briefly, in vivo experimental models allow the study of mechanisms, kinetics, and dynamics in the context of a complex organism.…”

Section: Insight Into the Angiogenic Tumor Ecosystemmentioning

confidence: 99%

Unraveling the Role of Angiogenesis in Cancer Ecosystems

2018

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Activation of the tumor and stromal cell-driven angiogenic program is one of the first requirements in the tumor ecosystem for growth and dissemination. The understanding of the dynamic angiogenic tumor ecosystem has rapidly evolved over the last decades. Beginning with the canonical sprouting angiogenesis, followed by vasculogenesis and intussusception, and finishing with vasculogenic mimicry, the need for different neovascularization mechanisms is further explored. In addition, an overview of the orchestration of angiogenesis within the tumor ecosystem cellular and molecular components is provided. Clinical evidence has demonstrated the effectiveness of traditional vessel-directed antiangiogenics, stressing on the important role of angiogenesis in tumor establishment, dissemination, and growth. Particular focus is placed on the interaction between tumor cells and their surrounding ecosystem, which is now regarded as a promising target for the development of new antiangiogenics.

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“…Having found that Mfn2 overexpression was beneficial to N2a cells in the setting of the TNFα-mediated inflammation microenvironment [40,41], we next looked at whether Yap, the downstream effector of Mfn2, was also involved in the survival of mouse neuroblastoma N2a cells. To this end, siRNA against Yap was transfected into Mfn2-overexpressed cells, and then cell viability was determined by the MTT assay.…”

Section: Knockdown Of Yap Abolishes the Protective Effect Of Mfn2 Ovementioning

confidence: 99%

Mitofusin-2 regulates inflammation-mediated mouse neuroblastoma N2a cells dysfunction and endoplasmic reticulum stress via the Yap-Hippo pathway

2019

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Endoplasmic reticulum (ER) stress is involved in inflammation-induced neurotoxicity. Mitofusin 2 (Mfn2), a member of the GTPase family of proteins, resides in the ER membrane and is known to regulate ER stress. However, the potential role and underlying mechanism of Mfn2 in inflammation-induced neuronal dysfunction is unknown. In our study, we explored the potential of Mfn2 to attenuate inflammation-mediated neuronal dysfunction by inhibiting ER stress. Our data show that Mfn2 overexpression significantly ameliorated tumor necrosis factor alpha (TNFα)-induced ER stress, as indicated by the downregulation of the ER stress proteins PERK, GRP78 and CHOP. Mfn2 overexpression also prevented the TNFα-mediated activation of caspase-3, caspase-12 and cleaved poly (ADP-ribose) polymerase (PARP). Cellular antioxidant dysfunction and reactive oxygen species overproduction were also improved by Mfn2 in the setting of TNFα in mouse neuroblastoma N2a cells in vitro. Similarly, disordered calcium homeostasis, indicated by disturbed levels of calcium-related proteins and calcium overloading, was corrected by Mfn2, as evidenced by the increased expression of store-operated calcium entry (SERCA), decreased levels of inositol trisphosphate receptor (IP3R), and normalized calcium content in TNFα-treated N2a cells. Mfn2 overexpression was found to elevate Yes-associated protein (Yap) expression; knockdown of Yap abolished the regulatory effects of Mfn2 on ER stress, oxidative stress, calcium balance, neural death and inflammatory injury. These results lead us to conclude that re-activation of the Mfn2-Yap signaling pathway alleviates TNFα-induced ER stress and dysfunction of mouse neuroblastoma N2a cells. Our findings provide a better understanding of the regulatory role of Mfn2-Yap-ER stress in neuroinflammation and indicate that the Mfn2-Yap axis may be a focus of research in terms of having therapeutic value for the treatment of neurodegenerative diseases.

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Mechanisms of angiogenesis in microbe-regulated inflammatory and neoplastic conditions

Cited by 127 publications

References 131 publications

Molecular Pharmacology of VEGF-A Isoforms: Binding and Signalling at VEGFR2

Molecular Pharmacology of VEGF-A Isoforms: Binding and Signalling at VEGFR2

Unraveling the Role of Angiogenesis in Cancer Ecosystems

Mitofusin-2 regulates inflammation-mediated mouse neuroblastoma N2a cells dysfunction and endoplasmic reticulum stress via the Yap-Hippo pathway

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