1521-0103/373/2/325–336$35.00 https://doi.org/10.1124/jpet.119.264192 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS J Pharmacol Exp Ther 373:325–336, May 2020 Copyright ª 2020 by The American Society for Pharmacology and Experimental Therapeutics Pre-eclamptic Fetal Programming Alters Neuroinflammatory and Cardiovascular Consequences of Endotoxemia in Sex-Specific Manners Salwa A. Abuiessa, Abdalla M. Wedn, Sahar M. El-Gowilly, Mai M. Helmy, and Mahmoud M. El-Mas Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt Received November 25, 2019; accepted February 12, 2020 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 consec- utive 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 admin- istration 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 pro- gramming 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 manifesta- tions 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 program- ming with endotoxemia. Introduction Pre-eclampsia (PE) is a new-onset gestational hypertensive status that is commonly associated with aggravated pro- teinuria, renal insufficiency, and impaired liver function (Brown et al., 2018). PE complicates almost 5% of all pregnancies (Morton, 2016) and negatively affects maternal and fetal health (Fox et al., 2019). Adverse fetal consequences involve antenatal risks of intrauterine growth restriction, preterm birth, and possibly fetal death in utero (Haddad et al., 2004; Madazli et al., 2014; Rezk et al., 2015). Moreover, in utero exposure to hypertensive state during pregnancy can result in long-term cardiovascular sequelae in offspring, including early onset hypertension, and increased risk of ischemic heart disease and stroke (Davis et al., 2012). The term “fetal programming” decribes developmental fetal adap- tations during pregnany with consequent cardiovascular, metabolic, and endocrine disorders in adulthood (Godfrey and Barker, 2001). During PE, the harsh intrauterine envi- ronment, induced by angiogenic, inflammatory, and hypoxic insults, causes genomic alterations in mother and fetus that would ultimately modify the expressed phenotype (Stojanov- ska et al., 2016). Fetal programming in response to prenatal stress alters offspring cardiovascular health. Litters of pre- natally stressed rats elicit exaggerated and more sustained elevations in BP and its variability, with female offspring showing more dramatic effects compared with their male counterparts (Igosheva et al., 2004). Supported by the Science and Technology Development Fund, Egypt (STDF Grants No. 14895 and 37026). The authors declare no conflict of interest. https://doi.org/10.1124/jpet.119.264192. ABBREVIATIONS: BP, blood pressure; BRS, baroreflex sensitivity; FFT, fast-Fourier transform; HF, high frequency; HR, heart rate; HRV, heart rate variability; LF, low frequency; LPS, lipopolysaccharide; LV, left ventricular; MAP, mean arterial pressure; MCP-1, monocyte chemoattractant protein-1; NTS, nucleus tractus solitarious; PE, pre-eclampsia; rMSSD, oot mean square of successive beat-to-beat differences in R-R interval durations; RVLM, rostral ventrolateral medulla; SBP, systolic blood pressure; SDNN, SD of beat-to-beat intervals; TLR-4, toll-like receptor 4. 325 at ASPET Journals on February 23, 2022 jpet.aspetjournals.org Downloaded from