Invasive trophoblasts generate regulatory collagen XVIII cleavage products

Endostatin, the C-terminal proteolytic fragment of the noncollagenous domain 1 (NC1) of the basement membrane protein collagen XVIII, inhibits cell proliferation and migration. Placental and decidual expression of the peptide suggested a role in angiogenesis and/or extravillous trophoblast differentiation. Here, we demonstrate that supernatants of trophoblastic SGHPL-5 cells, purified first trimester villous trophoblasts and villous explant cultures contain proteases which in vitro cleave 20 kDa endostatin from purified, recombinant NC1 domains. However, supernatants of decidual and villous fibroblasts failed to generate the 20 kDa endostatin fragment. Moreover, we show that recombinant endostatin inhibits invasion of SGHPL-5 cells through Matrigel invasion chambers. Since mesenchymal cells but not trophoblasts produce collagen XVIII we suspect that invasive trophoblasts may produce endostatin upon contacting the extracellular matrix deposited by decidual stromal cells. Generation of endostatin through trophoblast-derived proteases could play a role in the regulation of trophoblast invasiveness.