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(American Journal of Pathology. 2000;156:2185-2199.)
© 2000 American Society for Investigative Pathology

Regular Articles

Angiopoietin-1 and Angiopoietin-2 Activate Trophoblast Tie-2 to Promote Growth and Migration during Placental Development

From the Department of Reproductive and Vascular Biology, Division of Reproductive and Child Health, University of Birmingham, Birmingham Women’s Hospital, Birmingham, United Kingdom

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 (ED₂₇) and extravillous trophoblast-like (ED₇₇) properties, we show that the addition of Ang-2 (250 ng/ml) stimulated DNA synthesis in ED₂₇ trophoblast cells and triggered the release of NO. Ang-1 stimulated trophoblast (ED₇₇) 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.

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