Maternal and Fetal Defects of Gestational Angiotensin 1‐7 Receptor Antagonism: A Possible Preclinical Model of Preeclampsia

Abstract

Preeclampsia (PE) is a complex pathological state associated with serious adverse maternal and fetal consequences. Imbalances of the pressor ACE/Ang II and depressor ACE2/Ang 1-7 arms of renin-angiotensin system are implicated in PE pathophysiology. The current experimental study investigated whether the blockade of Ang 1-7 receptors (Mas receptors) during late pregnancy would replicate clinical features of PE. Two different dosing regimens of A779 (Mas receptor antagonist, 0.750 and 1.3 mg/kg/day s.c.) were administered daily to pregnant rats for 7 consecutive days starting from gestational day 14. The developed maternal and fetal abnormalities were compared to those produced by gestational L-NAME administration (50 mg/kg/day for 7 days), a standard model of PE in rodents. Gestational administration of L-NAME or A779 reduced weight and number of placentas and pups and increased death and resorption percentages of pups. These effects were more evident with the lower dose of A779 than with the higher dose. Moreover, A779 or L-NAME provoked similar elevations in systolic blood pressure and proteinuria. Immunohistochemical studies on placental tissues revealed enhanced protein expression of NFκB in dams treated with L-NAME or the lower, but not higher, dose of A779. While placental ACE expression remained unaltered, ACE2 expression was upregulated by A779 and L-NAME. Studies in isolated perfused kidneys demonstrated diminished acetylcholine vasodilation in L-NAME, but not A779, challenged preparations. Neither drug affected renal vasoconstriction induced by Ang II or phenylephrine. The current data highlight the likelihood of exploiting pregnant dams with pharmacologically eliminated Mas receptors for PE modeling in rodents. However, more studies are needed to further validate the model fidelity and its intimate resemblance to human PE.