title: Endostatin suppresses IGF-II-mediated signaling and invasion of human extravillous trophoblasts.
abstract: Endostatin, a biological active fragment of the extracellular matrix protein collagen XVIII, is known to interfere with cellular motility in the context of pathological angiogenesis. However, the physiological role of endostatin remains largely elusive. Recent evidence suggested that the inhibitor is produced in human decidual cells of early pregnancy, indicating that endostatin could be involved in diverse reproductive processes, such as implantation and/or placental differentiation. To gain more insights into the role of endostatin, we here analyzed its effects on trophoblast motility, proliferation, and signaling using purified primary trophoblasts, first-trimester villous explant cultures, and trophoblastic SGHPL-5 cells. In vitro Transwell assays demonstrated that purified endostatin inhibited both basal and IGF-II-induced migration and invasion as well as outgrowth from villous explant cultures. In contrast, basal and IGF-II-stimulated proliferation was unaffected upon addition of the inhibitor. Analyses of IGF-II-associated downstream signaling events showed that endostatin interfered with activation of various signaling kinases such as ERK1/2, protein kinase B (Akt)/mammalian target of rapamycin/p70 S6 kinase, and focal adhesion kinase. Furthermore, virus-mediated, stable gene silencing of Akt1 in SGHPL-5 cells using a micro-RNA-adapted short hairpin RNA-expressing plasmid revealed that endostatin-mediated inhibition of IGF-II-induced Akt phosphorylation was critically dependent on the expression of the particular isoform. In conclusion, the data suggest that endostatin could be a physiological inhibitor of IGF-II-dependent trophoblast cell motility by suppressing focal adhesion kinase/Akt/mammalian target of rapamycin/p70 S6 kinase signaling.
authors.affiliation: Medical University of Vienna, Department of Obstetrics and Fetal-Maternal Medicine, Reproductive Biology Unit, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Pollheimer
authors.forename: Peter
authors.initials: P
authors.lastname: Haslinger
authors.forename: Valerie
authors.initials: V
authors.lastname: Fock
authors.forename: Johanna
authors.initials: J
authors.lastname: Prast
authors.forename: Leila
authors.initials: L
authors.lastname: Saleh
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Biadasiewicz
authors.forename: Reidunn
authors.initials: R
authors.lastname: Jetne-Edelmann
authors.forename: Guttorm
authors.initials: G
authors.lastname: Haraldsen
authors.forename: Sandra
authors.initials: S
authors.lastname: Haider
authors.forename: Kora
authors.initials: K
authors.lastname: Hirtenlehner-Ferber
authors.forename: Martin
authors.initials: M
authors.lastname: Knöfler
mesh_terms: D002465:Cell Movement / Q000187:drug effects; D043169:Endostatins / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000378:metabolism*; D010920:Placenta / Q000187:drug effects / Q000378:metabolism; D011247:Pregnancy; D015398:Signal Transduction / Q000187:drug effects*; D014327:Trophoblasts / Q000187:drug effects* / Q000378:metabolism
chemical_list: D043169:Endostatins; D007335:Insulin-Like Growth Factor II