Angiotensin II mimics the hypoxic effect on regulating trophoblast proliferation and differentiation in human placental explant cultures.
Regulation of cytotrophoblast differentiation toward extravillous trophoblasts (EVTs) is critical for establishing successful pregnancy. Previous studies have focused primarily on the factors promoting the differentiation, while inhibitory regulators except hypoxia have been less documented. In this study, to test our hypothesis that angiotensin II (Ang II) would inhibit EVT differentiation, we investigated the effects of Ang II on trophoblast outgrowth and the expression of molecules associated with the proliferation and invasion of trophoblasts using human first trimester villous explant cultures. Ang II increased EVT outgrowth and the number of cells in cell columns. Moreover, Ang II-treated explants exhibited increased Ki67 and integrin alpha5 immunoreactivity in EVTs as well as matrix metalloproteinase-2 activity in the conditioned media, and decreased alpha1 integrin immunoreactivity, which are compatible with the features of the proliferative phenotype EVTs. These effects of Ang II were similar to those of hypoxia (3% O(2)). Ang II stimulated the expression of hypoxia inducible factor-1alpha at both mRNA and protein levels, and also enhanced the expression of plasminogen activator inhibitor-1 (PAI-1). Data presented herein suggest a possible role for Ang II in impairing trophoblast differentiation toward an invasive phenotype, which might be associated with shallow invasion in preeclamptic placentas.
Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
Masako
M
Araki-Taguchi
Seiji
S
Nomura
Kazuhiko
K
Ino
Seiji
S
Sumigama
Eiko
E
Yamamoto
Tomomi
T
Kotani-Ito
Hiromi
H
Hayakawa
Hiroaki
H
Kajiyama
Kiyosumi
K
Shibata
Atsuo
A
Itakura
Fumitaka
F
Kikkawa
D000293:Adolescent; D000328:Adult; D000804:Angiotensin II / Q000494:pharmacology*; D015153:Blotting, Western; D002452:Cell Count; D002454:Cell Differentiation / Q000187:drug effects*; D015687:Cell Hypoxia; D049109:Cell Proliferation / Q000187:drug effects*; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D039482:Integrin alpha5 / Q000096:biosynthesis; D019394:Ki-67 Antigen / Q000096:biosynthesis; D045726:Metalloproteases / Q000096:biosynthesis; D010100:Oxygen / Q000378:metabolism*; D010920:Placenta / Q000166:cytology / Q000187:drug effects; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014327:Trophoblasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D039482:Integrin alpha5; D019394:Ki-67 Antigen; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; C051321:SERPINE1 protein, human; D000804:Angiotensin II; D045726:Metalloproteases; D010100:Oxygen