title: Hyperinsulinemia increases placenta endothelin-converting enzyme-1 expression in trophoblasts.
abstract: BACKGROUND
  Exogenous hyperisulinemia causes pregnancy, induced hypertension and intrauterine growth restriction (IUGR) in pregnant rats. Hyperinsulinemia may increase production of endothelin-1 (ET-1), produced by sequential proteolysis of the big endothelin by the endothelin-converting enzyme (ECE)-1, the expression of which is examined here in the placenta, kidney, heart, and liver.
  
  
  METHODS
  Rats were rendered hyperinsulinemic by subcutaneous insulin pellet, mated and followed to the twenty-first day of pregnancy. They were then killed, and their fetuses and placentas were examined.
  
  
  RESULTS
  Hyperinsulinemic dams (HD) had higher blood pressure (BP) (130 ± 17 mm Hg in HD vs. 115 ± 16 mm Hg in normal pregnant dams (NPD), P < 0.05), lower placenta weight (0.44 ± 0.08 g in HD vs. 0.47 ± 0.08 NPD, P < 0.05) and lower fetus weight: males 4.9 ± 0.4 g in HD vs. 5.5 ± 0.4 g in NPD, P < 0.0001; females 4.7 ± 0.4 g in HD vs. 5.2 ± 0.4 g in NPD (P < 0.0001). ECE-1 expression as determined by western blot was significantly increased in the placenta and its implantation site, i.e., the mesometrial triangle (MT) of HD by 46 and 48%, respectively. In the kidney and heart of HD ECE-1, protein expression was increased by 230 and 220%, respectively, but its level in the liver was similar in both groups. Immunohistochemical staining revealed ECE-1 expression in endothelial cells and trophoblastic cells of the placenta and MT. Endothelin receptor A (ET-A), a mediator of vasoconstriction by ET-1, was also expressed in the endothelium and in trophoblasts of the placenta and MT. The expression of both ECE-1 and ET-A, as measured by automated image analysis, was generally stronger in placentas of HD.
  
  
  CONCLUSIONS
  ECE-1 and ET-A are expressed in the trophoblastic cells of the placenta and MT. This may affect local endothelin levels, BP and IUGR.
authors.affiliation: Institute of Endocrinology, Diabetes & Metabolism & Internal Medicine C, Rambam Medical Center & RB Rappaport Faculty of Medicine-Technion, Haifa, Israel. m_khamaisi@rambam.health.gov.il
authors.forename: Mogher
authors.initials: M
authors.lastname: Khamaisi
authors.forename: Galia
authors.initials: G
authors.lastname: Skarzinski
authors.forename: Judith
authors.initials: J
authors.lastname: Mekler
authors.forename: Farid
authors.initials: F
authors.lastname: Zreik
authors.forename: Rawan
authors.initials: R
authors.lastname: Damouni
authors.forename: Ilana
authors.initials: I
authors.lastname: Ariel
authors.forename: Michael
authors.initials: M
authors.lastname: Bursztyn
mesh_terms: D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000096:biosynthesis*; D000072396:Endothelin-Converting Enzymes; D005260:Female; D005317:Fetal Growth Retardation / Q000209:etiology; D006946:Hyperinsulinism / Q000503:physiopathology*; D008666:Metalloendopeptidases / Q000096:biosynthesis*; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A / Q000096:biosynthesis; D014327:Trophoblasts / Q000201:enzymology*
chemical_list: D044022:Receptor, Endothelin A; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes