Preeclamptic Programming Unevenly Modifies Hemodynamic and Renovascular Outcomes of Endotoxemia in Rat Offspring: Modulation by Sex and Antenatal Therapies

Abstract

Preeclampsia (PE) enhances the vulnerability of adult offspring to serious illnesses. The current study investigated whether preeclamptic fetal programming impacts hemodynamic and renovascular responsiveness to endotoxemia in adult male and female offspring and whether antenatal reprogramming therapy with pioglitazone and/or losartan favorably modulates these interactions. PE was induced by oral administration of L-NAME (50 mg/kg/day) to pregnant dams for seven days starting from gestational day 14. Adult offspring of either sex was treated with lipopolysaccharides (LPS, 5 mg/kg) followed 4 hr later by hemodynamic and renovascular studies. Tail-cuff measurements showed that while LPS produced no hemodynamic changes in female offspring, it significantly decreased blood pressure and increased heart rate in age-matched male counterparts. In isolated perfused kidneys of male offspring, PE or LPS reduced renal vasodilations elicited by acetylcholine (0.01-7.29 nmol) or N-ethylcarboxamidoadenosine (NECA, 1.6-100 nmol), effects that disappeared in PE/LPS kidney preparations. Likewise, elevations caused by LPS in serum inflammatory cytokines (TNFα and IL-1β) and renal biomarkers (BUN and creatinine) were attenuated in PE/LPS males. Contrary to males, NECA, but not acetylcholine, vasodilation was facilitated by LPS in female preparations, an effect that was comprised in PE/LPS kidneys. Gestational administration of pioglitazone or losartan reversed the attenuated acetylcholine/NECA vasodilations but failed to modify LPS hypotension or inflammation. Gestational treatment with combined pioglitazone/losartan therapy improved acetylcholine renal vasodilations and partly attenuated the inflammatory response. Our data suggest that preeclamptic fetal programming of endotoxic manifestations in adult offspring depends on animal sex and targeted biological activity and are partly improved by pharmacologic antenatal reprogramming with pioglitazone or losartan.