108
NF-κB pathway, and upregulated EZH2 leads to the induction of Ephrin-B2, a well-
known proangiogenic factor [ 179 ]. In addition, LANA stabilizes Notch signaling
and upregulates the Notch downstream factor Hey1 to achieve pathologic angiogen-
esis [ 180 ]. vGPCR (ORF74) activates JNK/SAPK and p38MAPK signaling cas-
cades and induces an angiogenic phenotype in infected cells [ 181 ]. VEGF expression
can also be enhanced by vGPCR through the stimulation of the activity of hypoxia-
inducible factor (HIF)-1 alpha [ 182 ]. vIL6 (ORF-K2) cooperates with vGPCR to
upregulate angiopoietin-2 (Ang2) through the mitogen-activated protein kinase
(MAPK) pathway [ 183 – 185 ], resulting in RAC1 activation, migration, and sprout-
ing angiogenesis [ 186 ]. The KSHV K1 protein induces the expression of VEGF and
matrix metalloproteinase-9 [ 187 ]. K15 recruits and activates PLCγ1 and down-
stream calcineurin and NFAT1 to induce RCAN1/DSCR1 expression and capillary
tube formation [ 188 ]. In addition, vFLIP and vGPCR induce the reprogramming of
lymphatic endothelial to mesenchymal transition (EndMT), which requires Notch
signaling and leads to the morphological differentiation of cells into capillary struc-
tures [ 148 ]. Therefore, KSHV directly induces the differentiation of infected cells
into an angiogenic phenotype (shown in Fig. 7.3).
During KSHV infection, viral or host cytokines are secreted and promote angio-genesis in a paracrine manner. The most important cytokine family is VEGF, the
expression of which is highly regulated by KSHV. The VEGF family has five mem-
bers: VEGF-A, placental growth factor (PGF), VEGF-B, VEGF-C, and
VEGF-D. KSHV-conditioned media contain VEGF-A and VEGF-B, which are suf-
ficient to induce the formation of angiogenic capillaries from cultured cells [ 189 ].
The mechanism by which KSHV induces VEGF may involve its ability to stabilize
HIF-1α [ 190 ], which binds the hypoxia-response elements (HRE) in the enhancers
of VEGF [ 191 ]. Ang1 and Ang2 are ligands that bind to the tyrosine kinase Tie2,
and the interaction between the ligands and receptors regulates angiogenesis. In KS,
Ang2 is upregulated and plays a role in vascular permeability and angiogenesis
[ 192 ]. Many other cytokines including interleukin 6 (IL-6) [ 193 ], CCL-2 [ 194 ], and
prostaglandin E2 [ 195 ] are induced and secreted by KSHV-infected cells to promote
neovascularization. In addition, KSHV encodes several unique cytokine-like factors
to stimulate angiogenesis. A viral homolog of interleukin 6 (vIL-6) assists to pro-
mote VEGF-A secretion [ 183 ]. Viral macrophage inflammatory proteins (vMIPs)
encoded by KSHV include three members. vMIP-II upregulates multiple proangio-
genic factors including VEGF in vivo [ 196 ]. vMIP-III functions as a CCR4 agonist
and stimulates angiogenesis [ 197 ]. These proangiogenic cytokines act on both
infected cells and neighboring uninfected cells to facilitate new vessel formation in
a paracrine manner.
In summary, proangiogenic cytokines, which are either host factors induced byviral infection or virus-encoded proteins, and the activation of the corresponding
signaling pathways create a permissive milieu that helps induce the formation of
new vessels, contributing to the highly vascularized feature of KS.
S. Li et al.