The regulation and localization of angiopoietin-1,-2, and their receptor Tie2 in normal and pathologic human placentae

Background: Angiopoietin-1 (Ang-1) and its antagonist angiopoietin-2 (Ang-2 ) act on the endothelial cell Tie-2 receptor to regulate vascular integrity and remodeling. The local balance of these factors and the level of other angiogenic factors determine whether blood vessels grow, are maintained or regress. Profound angiogenesis and vascular remodeling occur in the placent a and this is altered in preeclampsia, a major cause of maternal and fetal morbidity and mortality. Materials and Methods: The mRNAs encoding Ang-1, Ang-2 and Tie-2 were detec ted and localized in human placentae throughout gestation. The mechanism of regulation angiopoietin mRNAs level was determined by explant culture in a mbient and reduced oxygen, and in the presence of actinomycin D. Results: In situ hybridization showed that Ang-2 mRNA was abundant in the s yncytiotrophoblast in the first trimester of human pregnancy. Ang-1 mRNA co uld not be detected by in situ hybridization, but was by reverse transcript ase-polymerase chain reaction (RT-PCR) and Northern blotting. Placental vas cular structure is altered in preeclampsia and intrauterine growth restrict ion, conditions where feto-placental oxygenation is perturbed. In villous e xplant cultures, a reduction in oxygen tension significantly raised the lev els of Ang-2 mRNA, and this was dependent on transcription. However, simila r experiments showed that the stability of the Ang-1 message was greatly re duced under these conditions. Thus, hypoxia has opposite effects on Ang-1 a nd Ang-2 mRNA levels. Placentae obtained from women with preeclampsia had r educed levels of Ang-2 mRNA compared to gestationally matched controls. The re was no difference in the levels of Ang-1 mRNAs. Conclusions: These data show that the relative levels of Ang-1 and Ang-2 mR NA are regulated by local oxygen tension by different mechanisms and that t his may be important during normal human placentation.