CLASSIC CARDIOVASCULAR PROTECTIVE SIGNALING IN ANGIOTENSIN II-INDUCED NOVEL PREECLAMPSIA RAT MODEL

Objective: Angiotensin II (Ang II)-induces vasoconstriction, in vivo perfusion has been shown to induce preeclampsia (PE) in pregnant rats. In this study, we aimed to examine the protein and mRNA expressions of endothelial and neuronal NOS (eNOS, nNOS) as well as angiotensin II type 2 receptor (AT2R) in normal pregnant and Ang II-induced PE rats. Design and method: Pregnant (8 weeks) and non-pregnant SD rats (8 weeks, GD-8) were infused with Ang II via an osmotic minipump (1 ug/kg/min), and the rats (GD-21) were sacrificed 13 days later. Pregnant and non-pregnant rats without Ang II were taken as sham controls. The fetal weight, crown-rump length and placental weight of PE rats were significantly lower compared to those without Ang II infusion. Immunohistochemistry results showed an approximately 30% increase in glomerular volume, suggesting morphological changes in the kidney and Ang II infusion exhibits a PE phenotype. Results: Ang II infusion did not affect AT2R, AT1R and nNOS protein or mRNA expression in the uterus of non-pregnant or pregnant rats. However, eNOS mRNA expression was reduced in PE rats (p < 0.0001) although protein expression was not affected by Ang II infusion. However, in the placenta, AT1R and AT2R protein expression were not different in PE, but AT2R mRNA was decreased (p < 0.0001). eNOS protein was only expressed in fetal vascular endothelial cells, and eNOS protein expression was higher in PE rats (P = 0.001) but eNOS mRNA was decreased (p = 0.0096). Notably, strong nNOS expression was observed in placental trophoblast cell groups of sham and PE rats, and both mRNA and protein expression of nNOS was decreased in placental lysates of Ang II rats (respectively p = 0.0287 and p < 0.0001). Conclusions: These results demonstrate that we have recapitulated the PE model of Ang II infusion in rats. The expression of nNOS was reduced, and the localization of nNOS in the trophoblast suggested a new functional remodeling in the fetal vasculature. In the placenta, decreased expression of AT2R and nNOS may be a novel mechanism of impaired fetal development.