P275	Protein kinase C independent of phospholipase C or PI3-Kinase regulates placenta growth factor expression in endothelial cells.
P.Hewett, N.Lal, M.Cudmore, M.Ohba, S.Ahmad, A.Ahmed
Reproductive and Vascular Biology, The Medical School, University of Birmingham, Birmingham, GB.

Placenta growth factor (PlGF) promotes endothelial cell survival and angiogenesis via the Flt-1 receptor. Tumours implanted in mice lacking PlGF or expressing truncated/inactive Flt-1 show dramatically reduced growth and neovascularisation. As little is known of the cell type-specific expression or regulation of PlGF release we screened a panel of tumour cell lines including those derived from breast, colon and lung, as well as normal cells by ELISA and RT-PCR. Unlike vascular endothelial growth factor (VEGF), PlGF expression was low or below detectable levels in most of the tumour lines and non-transformed cells examined. In contrast high levels of PlGF mRNA and protein were detected in a range of human microvascular and large vessel endothelial cells suggesting a potential autocrine role for PlGF in tumour angiogenesis. Moreover, both basic fibroblast growth factor (bFGF) and VEGF increased PlGF release in human umbilical vein and dermal microvascular (HMEC-1) endothelial cells at a transcriptional level in a time and concentration-dependent manner. Basic FGF-mediated PlGF expression was blocked by pharmacological inhibitors of MEK (PD 98098) and PKC (Gö-6976, Ro-320432), and adenoviruses encoding dominant-negative mutants of PKCα and PKCε, but not through the inhibition of PLCγ, PI3-kinase or Ras. These results demonstrate the involvement of PKC and ERK signalling pathways in PlGF release. PlGF is an important factor in tumour progression and the characterisation of PlGF regulation in endothelial cells may provide new targets for vascular-mediated therapy.

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