RAS Imbalances Account for Baroreflex Dysfunction and Neuroinflammation Induced by Postpartum Endotoxemia in Weaning Preeclamptic Rats

Abstract

We recently reported that postpartum endotoxemia induced by lipopolysaccharides (LPS) provokes greater attenuation of arterial baroreflexes in weaning preeclamptic (PE) rats. Considering the role of renin‐angiotensin system (RAS) in PE programming, we investigated whether pharmacologic RAS modulation alters PE programming of baroreceptor dysfunction induced by endotoxemia. PE was induced by depriving pregnant rats of nitric oxide via gestational L‐NAME administration. RAS modulation involved gestational treatment with Ang 1‐7, losartan, pioglitazone, or combined losartan/pioglitazone. Arterial baroreflexes were assessed with the vasoactive method, which measures negative and positive chronotropism following blood pressure manipulations evoked by phenylephrine (PHE) or sodium nitroprusside (SNP). Slopes of the baroreflex curves were recruited as indicators of baroreflex sensitivity (BRSPHE and BRSSNP). All therapeutic regimens, but Ang 1‐7, abolished the rises in blood pressure seen in weaning PE dams. In contrast to no effect for losartan or pioglitazone, the shifts in baroreflex curves and reductions in BRSSNP in weaning PE/LPS mothers were reversed in dams treated gestationally with Ang 1‐7 or losartan/pioglitazone therapy. Alternatively, the concomitantly impaired BRSPHE was solely improved by the combined losartan/pioglitazone therapy. Immunohistochemical studies revealed upregulated TLR‐4/ACE expression and downregulated ACE2 expression in brainstem neuronal pools of PE/LPS rats. These effects were distinctly affected by gestational therapies as Ang 1‐7 reversed the altered brainstem expression of TLR‐4/ACE2, while gestational losartan/pioglitazone reversed the augmented ACE expression. Together, gestational targeting of offensive (ACE/Ang II (suppression) and defensive (ACE2/Ang 1‐7, facilitation) arms of RAS offers a reprogramming strategy against brainstem neuroinflammation and consequent baroreceptor depression caused by endotoxemia in weaning PE dams.