Kaposi's Sarcoma-Associated Herpesvirus Disrupts Adherens Junctions and Increases Endothelial Permeability by Inducing Degradation of VE-Cadherin

Qian, Liwu; Greene, Whitney; Ye, Fengchun; Gao, Shou‐Jiang

doi:10.1128/jvi.01042-08

Cited by 43 publications

(36 citation statements)

References 86 publications

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“…Moreover, KS-like lesion-associated blood vessels in mice presented with fenestrations, architectural vascular aberration and red blood cell extravasation, as determined by examining tissue morphology in control and vGPCRexpressing tumors (Figure 1e). This is consistent with previous studies (Montaner et al, 2003;Qian et al, 2008). To further quantify this vascular leakiness phenotype, a Miles assay was performed in vGPCRdriven tumors.…”

Section: Hhv8 Vgpcr-induced Tumors Display a Leaky Blood Vessel Networksupporting

confidence: 87%

Remodeling of VE-cadherin junctions by the human herpes virus 8 G-protein coupled receptor

et al. 2010

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Kaposi Sarcoma (KS) are opportunistic tumors, associated with human herpes virus 8 (HHV8) infection. KS development is highly favored by immune-depression and remains the second most frequent tumor in acquired immune deficiency syndrome patients. Although it has been shown that experimental expression of the HHV8 G-proteincoupled receptor (vGPCR) in the endothelial compartment is alone sufficient to recapitulate the formation and progression of KS-like lesions, its functional effects on endothelial homeostasis are not fully understood. Here we show that vGPCR expression in endothelial cells induces an increase in paracellular permeability both in vivo and in vitro. By using pharmacological inhibitors and small interference RNA-based knockdown, we demonstrate an essential role for the PI(3)Kinase-c/Rac nexus in vGPCRmediated permeability. This was further accompanied by dramatic remodeling of VE-cadherin-dependent cell-cell junctions. Importantly, this in vitro vGPCR-initiated signaling signature was observed in a large panel of human KS. Altogether, our results support the hypothesis that endothelial vGPCR signaling is co-opted in KS, and unveil new key cellular targets for therapeutic intervention.

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Section: Hhv8 Vgpcr-induced Tumors Display a Leaky Blood Vessel Networksupporting

confidence: 87%

Remodeling of VE-cadherin junctions by the human herpes virus 8 G-protein coupled receptor

et al. 2010

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“…Therefore, secreted virion particles play direct and important roles in angiogenesis. It has been noted that the KSHV infection of endothelial cells induces a number of other angiogenic and inflammatory cytokines, such as Ang-2, MMP1, MMP9, and IL-6 (47,48,64,65). Most likely, these proteins are upregulated via intracellular pathways that are altered as a result of KSHV infection.…”

Section: Discussionmentioning

confidence: 99%

“…Specifically, a number of recent studies have shown that the KSHV infection of endothelial cells induces angiogenesis and invasive phenotypes by inducing angiogenic and inflammatory cytokines, such as Ang-2, MMP1, MMP9, and IL-6 (47,48,64,65). A number of KSHV-encoded proteins, including K1, vGPCR, and vIL-6, have been reported to induce the major angiogenic factor VEGF-A, suggesting its involvement in KSHV pathogenesis (5,8,56,63).…”

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confidence: 99%

Kaposi's Sarcoma-Associated Herpesvirus Glycoproteins B and K8.1 Regulate Virion Egress and Synthesis of Vascular Endothelial Growth Factor and Viral Interleukin-6 in BCBL-1 Cells

Subramanian¹,

Sehgal

D’Auvergne

et al. 2010

J Virol

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Kaposi's sarcoma-associated herpesvirus (KSHV) viral glycoproteins play important roles in the infectious life cycle and have been implicated in KSHV-associated endothelial cell transformation, angiogenesis, and KS-induced malignancies. KSHV-associated primary effusion lymphomas (PELs) secrete high levels of vascular endothelial growth factor (VEGF) and viral interleukin-6 (vIL-6) in vitro and VEGF, vIL-6, and basic-fibroblast growth factor (b-FGF) in mouse xenografts. KSHV-encoded glycoproteins B (gB) and K8.1 stimulate VEGF secretion, most likely mediated by direct or indirect binding to cell surface receptors, including the gB-specific ␣V␤3 and ␣3␤1 integrins. In this study, the short interfering RNA (siRNA)-mediated inhibition of either gB or K8.1 transcription by anti-gB or -K8.1 siRNAs caused a substantial reduction in virion egress and a decrease in both vIL-6 and VEGF production. Similarly, the treatment of BCBL-1 cells with anti-gB or anti-K8.1 antibodies caused a substantial reduction in vIL-6 and VEGF production. Codon-optimized versions of either wild-type gB, mutant gB having the RGD amino acid motif changed to RAA, or K8.1 efficiently rescued virion egress and VEGF and vIL-6 production. These results suggest that the binding of gB via its RGD motif to integrin receptors was not responsible for the observed gB-associated regulation of VEGF and vIL-6 transcription. Conditioned medium collected from BCBL-1 cells transfected with anti-gB and anti-K8.1 siRNAs or treated with anti-gB and anti-K8.1 antibodies exhibited a significantly reduced ability to induce the formation of the capillary network of endothelial cells compared to the ability of medium from mock-infected BCBl-1 cells. Furthermore, medium obtained from BCBL-1 cells expressing smaller amounts of gB and K8.1 produced a substantial reduction in endothelial cell migration in a vertical migration assay compared to that of control medium containing wild-type levels of gB and K8.1. These results suggest a functional linkage between gB/K8

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“…Dengue virus (the cause of dengue hemorrhagic fever) and Karposi's sarcoma-associated herpesvirus (KSHV) have also been shown to downregulate VE-cadherin (21,29,37). In the case of KSHV it has been demonstrated that a viral protein which functions as a ubiquitin ligase targets VE-cadherin and causes its downregulation (29).…”

Section: Vol 84 2010 Hantavirus and Vascular Permeability 11231mentioning

confidence: 99%

Andes Virus Disrupts the Endothelial Cell Barrier by Induction of Vascular Endothelial Growth Factor and Downregulation of VE-Cadherin

Shrivastava-Ranjan

Rollin

Spiropoulou

2010

J Virol

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Hantavirus pulmonary syndrome (HPS) and hemorrhagic fever with renal syndrome (HFRS) are severe diseases associated with hantavirus infection. High levels of virus replication occur in microvascular endothelial cells but without a virus-induced cytopathic effect. However, virus infection results in microvascular leakage, which is the hallmark of these diseases. VE-cadherin is a major component of adherens junctions, and its interaction with the vascular endothelial growth factor (VEGF) receptor, VEGF-R2, is important for maintaining the integrity of the endothelial barrier. Here we report that increased secreted VEGF and concomitant decreased VE-cadherin are seen at early times postinfection of human primary lung endothelial cells with an HPS-associated hantavirus, Andes virus. Furthermore, active virus replication results in increased permeability and loss of the integrity of the endothelial cell barrier. VEGF binding to VEGF-R2 is known to result in dissociation of VEGF-R2 from VE-cadherin and in VE-cadherin activation, internalization, and degradation. Consistent with this, we showed that an antibody which blocks VEGF-R2 activation resulted in inhibition of the Andes virus-induced VE-cadherin reduction. These data implicate virus induction of VEGF and reduction in VE-cadherin in the endothelial cell permeability seen in HPS and suggest potential immunotherapeutic targets for the treatment of the disease.

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Kaposi's Sarcoma-Associated Herpesvirus Disrupts Adherens Junctions and Increases Endothelial Permeability by Inducing Degradation of VE-Cadherin

Abstract: Kaposi's sarcoma (KS) is a vascular tumor of proliferative endothelial cells caused by KS-associated herpesvirus

Cited by 43 publications

References 86 publications

Remodeling of VE-cadherin junctions by the human herpes virus 8 G-protein coupled receptor

Remodeling of VE-cadherin junctions by the human herpes virus 8 G-protein coupled receptor

Kaposi's Sarcoma-Associated Herpesvirus Glycoproteins B and K8.1 Regulate Virion Egress and Synthesis of Vascular Endothelial Growth Factor and Viral Interleukin-6 in BCBL-1 Cells

Andes Virus Disrupts the Endothelial Cell Barrier by Induction of Vascular Endothelial Growth Factor and Downregulation of VE-Cadherin

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