Pre-eclamptic Fetal Programming Alters Neuroinflammatory and Cardiovascular Consequences of Endotoxemia in Sex-Specific Manners

Pre-eclampsia (PE)-induced fetal programming predisposes offspring to health hazards in adult life. Here, we tested the hypothesis that pre-eclamptic fetal programming elicits sexually dimorphic inflammatory and cardiovascular complications to endotoxemia in adult rat offspring. PE was induced by oral administration of L-NAME (50 mg/kg per day for seven consecutive days) starting from day 14 of conception. Cardiovascular studies were performed in conscious adult male and female offspring preinstrumented with femoral indwelling catheters. Compared with non-PE male counterparts, intravenous administration of lipopolysaccharide (LPS, 5 mg/kg) to PE male offspring caused significantly greater 1) falls in blood pressure, 2) increases in heart rate, 3) rises in arterial dP/dtmax, a correlate of left ventricular contractility, and 4) decreases in time- and frequency-domain indices of heart rate variability (HRV). By contrast, the hypotensive and tachycardic actions of LPS in female offspring were independent of the pre-eclamptic state and no clear changes in HRV or dP/dtmax were noted. Measurement of arterial baroreflex activity by vasoactive method revealed no sex specificity in baroreflex dysfunction induced by LPS. Immunohistochemical studies showed increased protein expression of toll-like receptor 4 in heart as well as in brainstem neuronal pools of the nucleus of solitary tract and rostral ventrolateral medulla in endotoxic PE male, but not female, offspring. Enhanced myocardial, but not neuronal, expression of monocyte chemoattractant protein-1 was also demonstrated in LPS-treated male offspring. Together, pre-eclamptic fetal programming aggravates endotoxic manifestations of hypotension and autonomic dysfunction in male offspring via exacerbating myocardial and neuromedullary inflammatory pathways.

SIGNIFICANCE STATEMENT

Current molecular and neuroanatomical evidence highlights a key role for pre-eclamptic fetal programming in offspring predisposition to health hazards induced by endotoxemia in adult life. Pre-eclampsia accentuates endotoxic manifestations of hypotension, tachycardia, and cardiac autonomic dysfunction in male offspring via exacerbating myocardial and central inflammatory pathways. The absence of such detrimental effects in female littermates suggests sexual dimorphism in the interaction of pre-eclamptic fetal programming with endotoxemia.