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

Abstract

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 STATEMENTCurrent 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.

Intrauterine L-NAME Exposure Weakens the Development of Sympathetic Innervation and Induces the Remodeling of Arterial Vessels in Two-Week-Old Rats

“…A number of studies have shown that a similar effect of L-NAME is observed at higher doses [25][26][27]. Consistent with previous research [38], blood pressure elevation was observed in L-NAME-treated females despite a compensatory decrease in heart rate, which suggests an increase in peripheral vascular resistance. Importantly, peripheral vasoconstriction upon L-NAME treatment may be due to the inhibition of not only vascular eNOS [39], but also the nNOS of brain stem neurons responsible for cardiovascular control [3].…”

Implication of RAS in Postnatal Cardiac Remodeling, Fibrosis and Dysfunction Induced by Fetal Undernutrition

“…For example, in patients with preserved ejection fraction, this is a plausible mechanism leading to cardiomyocyte hypertrophy [46]. In addition, in a rat model of fetal programming induced by preeclampsia, myocardial inflammatory pathways have been described in males, but not in females [47]. 21-day old MUN males exhibited a normal ejection fraction, but diastolic dysfunction together with hypertrophy and fibrosis, and we have previously demonstrated that males, but not females, exhibit increased plasma oxidative damage biomarkers [12] and elevated cardiac NADPH oxidase expression [13].…”

Preventing Developmental Origins of Cardiovascular Disease: Hydrogen Sulfide as a Potential Target?

“…First, ADMA competes with Larginine to inhibit NO production [68] and its increase is involved in coronary artery disease [69], congenital heart disease [70], type 2 diabetes [71], stroke [72], obesity [73], and peripheral arterial occlusive disease [74]. Second, gestational NO depletion induced by N G -nitro-L-arginine-methyl ester (L-NAME, an inhibitor of NOS) causes cardiovascular programming in adult offspring, characterized as endothelial dysfunction, hypertension, defect of carotid artery, and cardiac hypotrophy [75,76]. Third, reprogramming effects of therapeutic strategies targeting the ADMA/NO pathway to prevent the developmental programming of hypertension have been reported in various animal models [76][77][78][79].…”