http://atvb.ahajournals.org/content/37/1/144?etoc=
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Abstract
Objective—Vascular
endothelial growth factor (VEGF), a major mediator of angiogenesis,
exerts its proangiogenic action by binding to VEGFR2 (VEGF receptor 2),
the activity of which is further modulated by VEGFR2 coreceptors such as
neuropilins. However, whether VEGFR2 is regulated by additional
coreceptors is not clear. To investigate whether SCUBE2 (signal
peptide-CUB-EGF domain-containing protein 2), a peripheral membrane
protein expressed in vascular endothelial cells (ECs) known to bind
other signaling receptors, functions as a VEGFR2 coreceptor and to
verify the role of SCUBE2 in the VEGF-induced angiogenesis.
Approach and Results—SCUBE2
lentiviral overexpression in human ECs increased and short hairpin RNA
knockdown inhibited VEGF-induced EC growth and capillary-like network
formation on Matrigel. Like VEGF, endothelial SCUBE2 was upregulated by
hypoxia-inducible factor-1α at both mRNA and protein levels. EC-specific
Scube2 knockout mice were not defective in vascular
development but showed impaired VEGF-induced neovascularization in
implanted Matrigel plugs and recovery of blood flow after hind-limb
ischemia. Coimmunoprecipitation and ligand-binding assays showed that
SCUBE2 forms a complex with VEGF and VEGFR2, thus acting as a coreceptor
to facilitate VEGF binding and augment VEGFR2 signal activity. SCUBE2
knockdown or genetic knockout suppressed and its overexpression promoted
the VEGF-induced activation of downstream proangiogenic and
proliferating signals, including VEGFR2 phosphorylation and
mitogen-activated protein kinase or AKT activation.
Conclusions—Endothelial SCUBE2 may be a novel coreceptor for VEGFR2 and potentiate VEGF-induced signaling in adult angiogenesis.
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