Placental growth factor neutralising antibodies give limited anti-angiogenic effects in an in vitro organotypic angiogenesis model |
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Authors: | Sandra R Brave Cath Eberlein Masabumi Shibuya Stephen R Wedge Simon T Barry |
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Institution: | (1) Cancer Bioscience, AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK;(2) Department of Molecular Oncology, Tokyo Medical and Dental University, Tokyo 113-8519, Japan;(3) Cancer and Infection Research, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK; |
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Abstract: | Vascular Endothelial Growth Factor Receptor (VEGFR) mediated signalling drives angiogenesis. This is predominantly attributed
to the activity of VEGFR-2 following binding of VEGF-A. Whether other members of the VEGFR and ligand families such as VEGFR-1
and its ligand Placental Growth Factor (PlGF) can also contribute to developmental and pathological angiogenesis is less clear.
We explored the function of PlGF in VEGF-A dependent angiogenesis using an in vitro co-culture assay in which endothelial
cells are cultured on a fibroblast feeder layer. In the presence of 2% FS MCDB media (containing limited growth factors) in
vitro endothelial tube formation is driven by endogenous angiogenic stimuli which are produced by the fibroblast and endothelial
cells. Under these conditions independent sequestration of either free VEGF-A or PlGF with polyclonal and monoclonal antibodies
inhibited tube formation suggesting that both ligands are required to drive an angiogenic response. Endothelial tube formation
could only be driven within this assay by the addition of exogenous VEGF-A, VEGF-E or VEGF-A/PlGF heterodimer, but not by
PlGF alone, implying that activation of either VEGFR-2/VEGFR-1 heterodimers or VEGFR-2 homodimers were responsible for eliciting
an angiogenic response directly, but not VEGFR-1 homodimers. In contrast to results obtained with an endogenous angiogenic
drive, sequestration of PlGF did not affect endothelial tube formation when the assay was driven by 1 ng/ml exogenous VEGF-A.
These data suggest that although neutralising PlGF can be shown to reduce endothelial tube formation in vitro, this effect
is only observed under restricted culture conditions and is influenced by VEGF-A. Such data questions whether neutralising
PlGF would have a therapeutic benefit in vivo in the presence of pathological concentrations of VEGF-A. |
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