ALPHA LIPOIC ACID TREATMENT AMELIORATES THE MATERNAL SYNDROME, PLACENTAL DYSFUNCTION AND FETAL GROWTH IN A RAT MODEL OF PREECLAMPSIA SUPERIMPOSED ON CHRONIC HYPERTENSION

BARRIENTOS GABRIELA; PAULA D PRINCE; GRACIELA GIARDINA; ANA UCEDA; MARIA ALEJANDRA SGARIGLIA; MONICA GALLEANO; GARCÍA, SILVIA INÉS

Chicago

Congreso; Scientific Sessions of the American Heart Association; 2022

AMERICAN HEART ASSOCIATION

ALPHA LIPOIC ACID TREATMENT AMELIORATES THE MATERNAL SYNDROME, PLACENTAL DYSFUNCTION AND FETAL GROWTH IN A RAT MODEL OF PREECLAMPSIA SUPERIMPOSED ON CHRONIC HYPERTENSIONGabriela Barrientos1,, Paula D Prince2, Graciela Giardina1, Ana Uceda1, Maria Alejandra Sgariglia1, Monica Galleano2, Silvia I García1,21 Laboratorio de Medicina Experimental, Hospital Alemán, Buenos Aires - CONICET, 2 Instituto de Bioquímica y Medicina Molecular (IBIMOL), UBA-CONICET, 3 Instituto de Investigaciones Médicas (IDIM), UBA-CONICET,  gbarrientos@hospitalaleman.comINTRODUCTIONWith a global prevalence of 1 to 5%, chronic hypertension during pregnancy contributes asignificant healthcare economic burden associated with poor maternal and perinatal outcomes. Adverse outcomes are mostly due to progression to superimposed preeclampsia (SPE), which occurs in 25-40% of pregnancies affected by chronic hypertension1. In previous studies, we have demonstrated that the Stroke-prone Spontaneously Hypertensive Rat (SHRSP) model for essential hypertension displays a SPE phenotype during pregnancy, characterized by early defects in trophoblast invasion leading in turn to placental dysfunction, asymmetric fetal growth restriction and a maternal syndrome with increased hypertension and proteinuria towards term2. Despite great research efforts during the past decade, the cellular and molecular pathways involved in SPE pathogenesis remain largely unknown.AIMSThe present study pursued two specific aims: 1) to investigate the involvement of placentaloxidative stress pathways in the sPE syndrome in pregnant SHRSP and 2) to evaluate thetherapeutic potential of alpha lipoic acid (αLA), a potent antioxidant, during early pregnancy in this model.MATERIALS AND METHODSSHRSP and Wistar Kyoto (WKY) females (10?12 weeks old, 200-250 g body weight, N = 6animals/day analyzed) were mated to congenic males and checked daily for vaginal plugs,denoted as gestation day (GD)1. Pregnant dams of both strains were assigned to two groups:αLA treatment, injected 25mg/kg body weight αLA i.p. at GD1, GD8 and GD12 and controls, injected saline following the same protocol. Systolic blood pressure (SBP) was determined premating and on the morning of GD1, 7, 10, 14, 18 and 20 using a noninvasive volume pressure recording device, as described previously2. On the selected dates, females were housed in metabolic cages for collection of 24 h urine samples. Following collection of blood samples, animals were euthanized and implantation sites isolated for morphological and western blot analyzes. Fetal and placental weights were recorded on GD18 and GD20. Statistical comparisons were performed with either unpaired t tests or two-way ANOVA and Bonferroni post-hoc tests, run using GraphPad Prism v 7.0. A p value of less than 0.05 was considered statistically significant.RESULTSCompared to WKY, SHRSP placentas displayed signs of oxidative stress including significantly increased immunolabeling for nytrotirosine residues and increased levels of thiobarbituric acid reactive substances (TBARS, Fig. 1A) together with decreased expression of antioxidant Mn-SOD and peroxiredoxin at GD14, at the onset of the maternal sPE syndrome. Notably, treatment with αLA prevented the pregnancy-dependent SBP increase typical of the SHRSP model (Fig 1B), decreased significantly the maternal protein excretion levels at GD18 and restored platelet counts and serum free hemoglobin levels at GD20. Furthermore, treatment with αLA significantly increased the SHRSP fetal weights and crown-rump lengths and ameliorated the asymmetric growth restriction phenotype, as demonstrated by the significant decrease of cephalization indexes observed at GD20 (Fig 1C). The placental phenotype was also improved in αLA-treated SHRSP, as noted by the increased accumulation of Aldh1a3-expressing glycogen trophoblasts in the junctional zone at GD14 together with increased placental weights observed at GD20 (Fig 1C, lower panel).CONCLUSIONOnset of SPE is associated with exacerbated lipoperoxidation and nitro-oxidative stress in the SHRSP placenta. Treatment with αLA during early pregnancy prevented development of the maternal syndrome and ameliorated placental function and fetal growth, emerging as a novel tool for prevention of superimposed preeclampsia in pregnancies affected by chronichypertension.REFERENCES1 Chappell, L. C. et al. Adverse perinatal outcomes and risk factors for preeclampsia in women with chronic hypertension: a prospective study. Hypertension 51, 1002-1009,doi:10.1161/HYPERTENSIONAHA.107.107565 (2008).2 Barrientos, G. et al. Defective trophoblast invasion underlies fetal growth restriction andpreeclampsia-like symptoms in the stroke-prone spontaneously hypertensive rat. Molecular human reproduction 23, 509-519, doi:10.1093/molehr/gax024 (2017).