Exogenous hyperisulinemia causes intrauterine growth restriction (IUGR) and abrogation of the normal gestational blood pressure (BP) decline in rats, associated with shallower implantation site (mesometrial triangle, MT). We demonstrated altered expression of nitric oxide synthase (NOS) system in the placenta and MT of hyperinsulinemic dams (HD). We investigated the endothelin system, which counteracts the vasodilating effect of NO, in our IUGR rat model.

Rats were rendered hyperinsulinemic, mated and followed to pregnancy day 21. Endothelin-converting enzyme (ECE)-1 expression was examined by western blot in the placenta and MT, kidneys, heart and liver of HD. Immunostaining for ECE-1 and endothelin receptor A (ET-A) was quantified by an automated image analysis system.

HD had higher BP than normal pregnant dams (NPD) (130±17mmHg in HD vs. 115±16mmHg in NPD, p<0.05), lower placenta weight (0.44±0.08g in HD vs. 0.47±0.08 NPD, p< 0.05) and reduced fetal weight (males 4.9±0.4g in HD vs. 5.5±0.4g in NPD, p<0.0001; females 4.7±0.4g in HD vs. 5.2±0.4g in NPD, p<0.0001). ECE-1 protein expression was significantly increased in the placenta and the MT of HD by 46% and 48%, respectively, and in the kidney and heart of HD by 230% and 220%, respectively, but not in the liver. Immunostaining revealed expression of ECE-1 and its receptor ET-A, a mediator of vasoconstriction, in trophoblasts of the placenta, MT and endovascular trophoblasts.

Conclusion: ECE-1 and ET-A, mediators of vasoconstriction, are expressed in trophoblastic cells in the placenta and MT. Their overexpression in HD may affect local endothelin levels, and may be one of the factors leading to IUGR.

Authors:

I Ariel, M Khamaisi, G Skarzinski, M Bursztyn.
Departments of Pathology and Medicine, Hadassah Hebrew-University Medical Center, Mount-Scopus, Jerusalem; Institute of Endocrinology, Diabetes & Metabolism 
& Internal Medicine C, Rambam Medical Center & RB Rappaport Faculty of Medicine, Technion, Haifa.