The effects of angiogenic growth factors on extravillous trophoblast invasion and motility

There is accumulating evidence that deficient trophoblast invasion of the p lacental bed spiral arteries is crucial to the pathogenesis of pre-eclampsi a and intrauterine growth restriction. However, the factors which regulate the process of trophoblast invasion remain unclear. We have investigated wh ether extravillous trophoblast invasion and motility are mediated by the an giogenic growth factors, vascular endothelial growth factor (VEGF) :md plac ental growth factor (P1GF). The SGHPL-4 extravillous trophoblast cell line was utilized. Expression of mRNA for the receptors of VEGF and PIGF (KDR and fit-1) was determined usin g the reverse transcriptase polymerase chain reaction. An in vitro model of invasion assessed the number and length of trophoblast processes invading into an extracellular matrix. The motility of cells under standard culture conditions was also quantified. The effect of the addition of VEGF and PIGF ( +/- heparin) on trophoblast invasion and motility was determined. The ef fect of VEGF and PIGF ( +/- heparin) on SGHPL-4 cell proliferation was asse ssed by cell counts at 24, 48 and 72 h post-addition of growth factor. The SGHPL-4 cells expressed mRNA for the fit-1 but not the KDR receptor. Th e addition of VEGF resulted in a significant decrease in the number of trop hoblast processes formed (P < 0.02); this effect was not influenced by the addition of heparin. However, there was no effect on the length of processe s formed in response to VEGF ( +/- heparin). The addition of P1GF had no ef fect on either the number or the length of processes formed. The addition o f VEGF increased the motility of the SGHPL-4 cells (P < 0.002); the additio n of heparin prevented this VEGF-induced increase in motility. The addition of P1GF had no effect on SGHPL-4 motility (+/- heparin). Neither growth fa ctor had any effect on the proliferative ability of SGHPL-4 cells. Contrary to our hypothesis, we did not find that the angiogenic growth fact ors, VEGF and P1GF, mediated the in vitro invasion of trophoblast cells int o an extracellular matrix. However, VEGF did increase trophoblast motility. Our findings of an effect of VEGF on trophoblast motility (and possibly in vasion) suggests the presence of functional receptors, which can mediate th e actions of VEGF. Caution must be exercised before any extrapolation to th e in vivo situation, however, it could be speculated that the increased mot ility in response to VEGF may be an initial response to attract trophoblast cells to the decidua, and that VEGF might then limit the degree to which t rophoblast cells invade. (C) 1999 Harcourt Publishers Ltd.