Vascular Endothelial Growth Factor Receptor 2 (VEGFR2/KDR) Promotes KSHV Lytic Replication and Drives Pro‐Inflammatory Cytokine Release and Cancer Signaling

Expression of vascular endothelial growth factor receptor 2 (VEGFR2/KDR) is elevated in Kaposi Sarcoma lesions and is a key driver of vasculogenesis and angiogenesis. Increased levels of KDR are associated with several cancers and has been linked to the oncogenic potential of Kaposi sarcoma herpesvirus (KSHV)-infected cells. However, the functional role of KDR in KSHV infection requires further exploration. Here, we have demonstrated the importance of KDR expression in KSHV infection and assessed the effects of KDR loss-of-function in KSHV lytic replication and the corresponding host response in de novo infected primary lymphatic endothelial cells (LEC). KDR was found to promote lytic replication, stimulate the release of pro-inflammatory cytokines, and upregulate cancer signaling pathways. As such, we propose a model in which elevated KDR in KS lesions supports a lytic program to ensure maintenance and spread of infected cells while also promoting the tumor microenvironment.