title: Endothelin-1 stimulates proliferation of first-trimester trophoblasts via the A- and B-type receptor and invasion via the B-type receptor.
abstract: BACKGROUND
  Endothelin-1 (ET-1) stimulates proliferation and invasion of first-trimester human trophoblast cells.
  
  
  OBJECTIVE
  To test the hypothesis that ET-1 effects are mediated by different receptor subtypes [ET receptor (ETR)-A and ETR-B].
  
  
  METHODS
  The location of ETR in trophoblast cell columns (wk 6-12) was investigated by immunohistochemistry and autoradiography. Trophoblasts were isolated from first-trimester human placentas and proliferative and invasive subpopulations separated using an integrin α6 antibody. Cells were incubated for 24 h with 10 μm ET-1 and different ETR antagonists: PD142893 (unselective), BQ-610 (ETR-A), and RES-701-1 (ETR-B). After ETR down-regulation by antisense oligonucleotides, proliferation (thymidine incorporation, protein synthesis) and invasion (Matrigel invasion) were measured. ETR expression in isolated cells was analyzed by Western blotting and semiquantitative RT-PCR.
  
  
  RESULTS
  Both ETR are expressed in both subpopulations in the cell column with predominance of ETR-A in the proximal part and proliferative subpopulation, whereas ETR-B is present at similar levels in both subpopulations. These results were confirmed at the mRNA level. ET-1 increased proliferation (maximum 267% of control) and invasion (maximum 288% of control) of first-trimester trophoblasts. The mitogenic ET-1 effect was inhibited (P < 0.05) by 40-80% with each receptor antagonist and by 44 and 40%, respectively, by ETR-A and ETR-B antisense oligonucleotides. The invasion-promoting effect was almost completely blocked in the presence of the ETR-B antagonists.
  
  
  CONCLUSIONS
  The effect of ET-1 on cell proliferation in first-trimester trophoblasts is mediated by both ETR, whereas its effect on invasion is mediated predominantly by ETR-B. These effects are in line with the receptor subtype location.
authors: Department of Obstetrics and Gynecology, Medical University of Graz, Auenbruggerplatz 14, A-8036 Graz, Austria. mila.cervarzivkovic@medunigraz.at
authors: M
authors: M
authors: Cervar-Zivkovic
authors: M
authors: M
authors: Dieber-Rotheneder
authors: S
authors: S
authors: Barth
authors: T
authors: T
authors: Hahn
authors: G
authors: G
authors: Kohnen
authors: B
authors: B
authors: Huppertz
authors: U
authors: U
authors: Lang
authors: G
authors: G
authors: Desoye
mesh_terms: D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects; D019332:Endothelin-1 / Q000494:pharmacology*; D005260:Female; D006801:Humans; D010920:Placenta / Q000187:drug effects / Q000378:metabolism; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D012333:RNA, Messenger / Q000378:metabolism; D044022:Receptor, Endothelin A / Q000378:metabolism*; D044023:Receptor, Endothelin B / Q000378:metabolism*; D014327:Trophoblasts / Q000187:drug effects* / Q000378:metabolism
chemical_list: D019332:Endothelin-1; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B