Human placental vascular development: vasculogenic and angiogenic (branching and nonbranching) transformation is regulated by vascular endothelial growth factor-A, angiopoietin-1, and angiopoietin-2.
During placental development, vessel formation occurs initially by vasculogenesis and subsequently by branching and nonbranching angiogenesis. We investigated vascular endothelial growth factor (VEGF)-A, angiopoietin (Ang)-1 and -2 transcript profiles, and the protein products that they encode in placentas from normotensive pregnancies throughout pregnancy. In addition, we compared these genes in placentas from normotensive women and those with preeclampsia during the third trimester. Quantitative real-time PCR analysis demonstrated that VEGF-A and Ang1 mRNA increased in a linear pattern by 2.5 (not significant) and 2.8%/wk (P = 0.034), respectively, whereas Ang2 decreased logarithmically by 3.5%/wk (P = 0.0003). Ang2 mRNA was 400- and 100-fold higher than Ang1 and VEGF-A, respectively, in the first trimester and declined to 20-fold and 7-fold in the third. Ang2 protein (ELISA) decreased by 4.7%/wk (P = 0.0001), whereas Ang1 and VEGF-A were undetectable. In preeclampsia compared with normotensive pregnancy, only VEGF-A mRNA increased significantly, by 3-fold (P = 0.006). This increase may be related to low oxygen tension, as VEGF-A is up-regulated by hypoxia. In situ hybridization and immunohistochemical studies revealed that VEGF-A was localized in cyto- and syncytiotrophoblast and perivascular cells, whereas Ang1 and Ang2 were only in syncytiotrophoblast and perivascular cells in the immature intermediate villi during the first and second trimesters, and mature intermediate and terminal villi during the third trimester. These data suggest that these molecules may play important roles in placental biology and chorionic villus vascular development and remodeling in an autocrine/paracrine manner. The tight correlation between Ang2 mRNA and protein indicates that regulation of placental vascular development occurs at the transcriptional, and not translational, level.
Geva
Eli
E
Center for Reproductive Sciences, Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, San Francisco, California 94143-0556, USA.
Ginzinger
David G
DG
Zaloudek
Charles J
CJ
Moore
Dan H
DH
Byrne
Annette
A
Jaffe
Robert B
RB
D042683:Angiopoietin-1; D042702:Angiopoietin-2; D001483:Base Sequence; D001794:Blood Pressure; D017931:DNA Primers; D016228:Endothelial Growth Factors / Q000235:genetics*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000502:physiology; D008562:Membrane Glycoproteins / Q000235:genetics*; D018919:Neovascularization, Physiologic / Q000235:genetics*; D010920:Placenta / Q000098:blood supply* / Q000166:cytology; D016133:Polymerase Chain Reaction; D011247:Pregnancy / Q000502:physiology*; D011506:Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics*; D012016:Reference Values; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D042461:Vascular Endothelial Growth Factor A
C467630:ANGPT1 protein, human; D042683:Angiopoietin-1; D042702:Angiopoietin-2; D017931:DNA Primers; D016228:Endothelial Growth Factors; D008562:Membrane Glycoproteins; D011506:Proteins; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A