title: Angiopoietin-1 and angiopoietin-2 activate trophoblast Tie-2 to promote growth and migration during placental development.
abstract: Human placental development involves coordinated angiogenesis and trophoblast outgrowth that are compromised in intrauterine growth restriction (IUGR). As Tie-2((-/-)) mice exhibit growth retardation and vascular network malformation, the expression of Tie-2 and its ligands, angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2), were investigated in human placenta from normal pregnancies and those complicated by severe IUGR. Ribonucleotide protection assays showed no significant change in the expression of Ang-2 mRNA between gestationally matched normal and IUGR placentas; however, immunoblots revealed that Ang-2 protein was significantly decreased in IUGR, suggesting that this may contribute to the abnormal development of the villous vasculature. In situ hybridization studies showed that Ang-1 and Tie-2 were detected in the cyto/syncytiotrophoblast bilayer in first-trimester placenta, whereas Ang-2 mRNA was restricted to the cytotrophoblast, suggesting their role in trophoblast function. At term, Ang-1 mRNA and immunoreactive protein were restricted to the paravascular tissues of the primary stem villi, supporting its role in vessel maturation. In contrast, Ang-2 was expressed throughout the term villous core, perhaps to permit the developing placental vascular network to remain in a state of fluidity. As these studies also revealed that trophoblast, in addition to endothelial cells, expressed Tie-2 receptors, we investigated the potential role of Ang-1/Ang-2 on trophoblast proliferation, migration, and the release of NO. Using spontaneously transformed first-trimester trophoblast cell lines that exhibit cytotrophoblast-like (ED(27)) and extravillous trophoblast-like (ED(77)) properties, we show that the addition of Ang-2 (250 ng/ml) stimulated DNA synthesis in ED(27) trophoblast cells and triggered the release of NO. Ang-1 stimulated trophoblast (ED(77)) migration in a dose-dependent manner that was inhibited by recombinant Tie-2-FC. These data thus imply, for the first time, a specific role for angiopoietins as regulators of trophoblast behavior in the development of the utero/fetoplacental circulation, an action independent of their well-established roles in vascular endothelium.
authors.affiliation: Department of Reproductive and Vascular Biology, University of Birmingham, Birmingham Women's Hospital, United Kingdom.
authors.forename: C
authors.initials: C
authors.lastname: Dunk
authors.forename: M
authors.initials: M
authors.lastname: Shams
authors.forename: S
authors.initials: S
authors.lastname: Nijjar
authors.forename: M
authors.initials: M
authors.lastname: Rhaman
authors.forename: Y
authors.initials: Y
authors.lastname: Qiu
authors.forename: B
authors.initials: B
authors.lastname: Bussolati
authors.forename: A
authors.initials: A
authors.lastname: Ahmed
mesh_terms: D042683:Angiopoietin-1; D042702:Angiopoietin-2; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D005260:Female; D005317:Fetal Growth Retardation / Q000378:metabolism; D006801:Humans; D007158:Immunologic Techniques; D017403:In Situ Hybridization; D008562:Membrane Glycoproteins / Q000235:genetics / Q000494:pharmacology*; D009363:Neoplasm Proteins / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism; D010920:Placenta / Q000378:metabolism / Q000502:physiology*; D011247:Pregnancy; D011506:Proteins / Q000235:genetics / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger / Q000378:metabolism; D042787:Receptor, TIE-2; D012016:Reference Values; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014018:Tissue Distribution; D014327:Trophoblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism
chemical_list: C467630:ANGPT1 protein, human; D042683:Angiopoietin-1; D042702:Angiopoietin-2; C105373:MEN1 protein, human; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D009569:Nitric Oxide; D042787:Receptor, TIE-2