Abstract
Preeclampsia (PE)-induced fetal programming predisposes offspring to health hazards in adult life. Here, we tested the hypothesis that preeclamptic 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/day for 7 consecutive days) starting from day 14 of conception. Cardiovascular studies were performed in conscious adult male and female offspring pre-instrumented with femoral indwelling catheters. Compared with non-PE male counterparts, intravenous (i.v.) administration of lipopolysaccharide (LPS, 5 mg/kg) to PE male offspring caused significantly greater (i) falls in blood pressure (BP), (ii) rises in heart rate (HR) and left ventricular contractility (dP/dtmax), and (iii) decreases in time- and frequency-domain indices of heart rate variability. By contrast, the hypotensive and tachycardic actions of LPS in female offspring were independent of the preeclamptic state and no clear changes in heart rate variability or left ventricular function were noted. Measurement of arterial baroreflex activity by the vasoactive method revealed no sex specificity in baroreflex dysfunction induced by LPS. Immunohistochemical studies showed increased protein expression of toll-like receptor 4 (TLR-4) in the heart as well as in brainstem neuronal pools of the nucleus of the 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(MCP-1) was also demonstrated in LPS-treated male offspring. Together, preeclamptic 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 preeclamptic fetal programming in offspring predisposition to health hazards induced by endotoxemia in adult life. Preeclampsia 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 preeclamptic fetal programming with endotoxemia.
- blood pressure
- cardiovascular disease
- endotoxins
- fetal toxicology
- inflammation
- neuroimmunology
- septic shock
- The American Society for Pharmacology and Experimental Therapeutics