Gestationally Administered RAS Modulators Reprogram Endotoxic Cardiovascular and Inflammatory Profiles in Adult Offspring of Preeclamptic Rats

Abstract

Preeclampsia (PE) adversely programs fetal cardiovascular integrity and amplifies cardiovascular dysfunction induced by endotoxemia in adult offspring of preeclamptic mothers. Here, we asked if such aggravated endotoxic insult could be nullified by modulators of the renin-angiotensin system (RAS). PE was induced by gestational administration of L-NAME, a nitric oxide synthase inhibitor. Adult male offspring of PE mothers treated gestationally with Ang 1-7 (Ang II-derived vasodilator), losartan (AT1 receptor antagonist), pioglitazone (RAS modulator), or combined losartan/pioglitazone, were instrumented with femoral indwelling catheters and challenged intravenously with a 5 mg/kg dose of lipopolysaccharides (LPS, 5 mg/kg). LPS caused significant increases in heart rate and decreases in blood pressure and spectral index of overall heart rate variability. These effects were similarly reduced by all drug therapies. In offspring born to Ang 1-7-treated dams, the spectral index of cardiac sympathovagal balance showed elevated sympathetic dominance in response to LPS. Further, pioglitazone and its combination with losartan were more effective than Ang 1-7 or losartan in depressing the LPS-evoked increases in left ventricular contractility (dP/dtmax). Immunohistochemical studies revealed that Ang1-7, but not losartan/pioglitazone, regimen abolished the exaggerated increases in TLR-4 expression caused by PE/LPS in heart tissues and neuronal circuits of brainstem rostral ventrolateral medulla. By contrast, ACE expression in the same two areas was reduced by losartan/pioglitazone but not Ang 1-7. Together, gestational fetal reprogramming of Ang II (depression) and Ang 1-7 (activation) arms of RAS effectively counterbalance worsened endotoxic cardiovascular and inflammatory profiles in adult offspring of PE rats.