Kaposi's sarcoma-associated herpesvirus induces rapid release of angiopoietin-2 from endothelial cells

Kaposi sarcoma-associated herpesvirus (KSHV) stimulates proliferation, angiogenesis, and inflammation to promote Kaposi sarcoma (KS) tumor growth, which involves various growth factors and cytokines. Previously, we found that KSHV infection of human umbilical vein endothelial cells (HUVECs) induces...

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Veröffentlicht in:Journal of virology Jg. 87; H. 11; S. 6326
Hauptverfasser: Ye, Feng-Chun, Zhou, Fu-Chun, Nithianantham, Stanley, Chandran, Bala, Yu, Xiao-Lan, Weinberg, Aaron, Gao, Shou-Jiang
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 01.06.2013
Schlagworte:
Angiopoietin-2 - metabolism
Calcium - metabolism
Endothelial Cells - enzymology
Endothelial Cells - metabolism
Endothelial Cells - virology
Focal Adhesion Protein-Tyrosine Kinases - genetics
Focal Adhesion Protein-Tyrosine Kinases - metabolism
Herpesvirus 8, Human - genetics
Herpesvirus 8, Human - physiology
Humans
Integrins - metabolism
Phosphorylation
Sarcoma, Kaposi - enzymology
Sarcoma, Kaposi - genetics
Sarcoma, Kaposi - metabolism
Sarcoma, Kaposi - virology
ISSN:1098-5514, 1098-5514
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Zusammenfassung:Kaposi sarcoma-associated herpesvirus (KSHV) stimulates proliferation, angiogenesis, and inflammation to promote Kaposi sarcoma (KS) tumor growth, which involves various growth factors and cytokines. Previously, we found that KSHV infection of human umbilical vein endothelial cells (HUVECs) induces a transcriptional induction of the proangiogenic and proinflammatory cytokine angiopoietin-2 (Ang-2). Here, we report that KSHV induces rapid release of Ang-2 that is presynthesized and stored in the Weibel-Palade bodies (WPB) of endothelial cells upon binding to its integrin receptors. Blocking viral binding to integrins inhibits Ang-2 release. KSHV binding activates the integrin tyrosine kinase receptor signaling pathways, leading to tyrosine phosphorylation of focal adhesion kinase (FAK), the tyrosine kinase Src, and the Calα2 subunit of the l-type calcium channel to trigger rapid calcium (Ca(2+)) influx. Pretreatment of endothelial cells with specific inhibitors of protein tyrosine kinases inhibits KSHV-induced Ca(2+) influx and Ang-2 release. Inhibition of Ca(2+) mobilization with calcium channel blockers also inhibits Ang-2 release. Thus, the interaction between KSHV and its integrin receptors plays a key role in regulating rapid Ang-2 release from endothelial cells. This finding highlights a novel mechanism of viral induction of angiogenesis and inflammation, which might play important roles in the early event of KS tumor development.
Bibliographie:ObjectType-Article-1
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ISSN:1098-5514
1098-5514
DOI:10.1128/JVI.03303-12