Browsing by Autor "Houck, Julie A"

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Dysregulated Fatty Acid Metabolism in Preeclampsia Among Highland Andeans: Insights Into Adaptive and Maladaptive Placental Metabolic Phenotypes.
(2025) O'Brien, Katie A; Toledo-Jaldin, Lilian; Gu, Wanjun; Houck, Julie A; Lazo-Vega, Litzi; Miranda-Garrido, Valquiria; Yung, Hong W; Yasini, Hussna; Moore, Lorna G; Reisz, Julie A; Simonson, Tatum S; Shortt, Jonathan; Stalker, Margaret; D'Alessandro, Angelo; Julian, Colleen G
High-altitude pregnancy presents the complex physiological challenge of fulfilling maternal, placental, and fetal metabolic demands under chronic ambient hypoxia. Highland Andeans exhibit signs of adaptation to high-altitude hypoxia, showing relative protection against altitude-associated fetal growth restriction (FGR) and the positive selection of metabolic genes linked to placental mitochondrial capacity. Not all infants are protected, with both FGR and preeclampsia occurring among highland-resident Andeans. In Andeans, placental metabolic dysfunction is evident. By integrating metabolomic studies of maternal-placental-fetal triads with adaptive genetic signals in the fetal genome, we sought to identify adaptive and maladaptive placental metabolic phenotypes in highland Andeans (La Paz, Bolivia; 3850 m), including normotensive and preeclamptic pregnancies. Widespread differences in metabolite abundance were evident between normotensive and preeclamptic pregnancy across maternal, placental, and fetal compartments. Preeclampsia was characterized by a pronounced accumulation of fatty acid derivatives, specifically medium and long-chain acylcarnitines; these were also associated with low birth weight. Genotype-phenotype association analyses revealed novel links between putatively adaptive fetal haplotypes and placental metabolite abundance. Carriers of specific adaptive fetal haplotypes comprising genes linked to lipid metabolism had a greater abundance of placental short-chain acetyl-carnitine alongside decreased levels of linolenic acid (CPT2/LRP8), lower levels of the medium-chain octanoylcarnitine (EXOC4), and greater abundance of free carnitine (LIPG). Collectively, our study reveals a distinct metabolic phenotype in Andean preeclampsia characterized by incomplete fatty acid oxidation and highlights novel links between putatively adaptive fetal haplotypes and healthy placental metabolic phenotypes.
Vascular Disorders of Pregnancy Increase Susceptibility to Neonatal Pulmonary Hypertension in High-Altitude Populations.
(2022) Heath-Freudenthal, Alexandra; Toledo-Jaldin, Lilian; von Alvensleben, Inge; Lazo-Vega, Litzi; Mizutani, Rodrigo; Stalker, Margaret; Yasini, Hussna; Mendizabal, Fanny; Dorado Madera, Jesus; Mundo, William; Castro-Monrroy, Melany; Houck, Julie A; Moreno-Aramayo, Any; Miranda-Garrido, Valquiria; Su, Emily J; Giussani, Dino A; Abman, Steven H; Moore, Lorna G; Julian, Colleen G
BACKGROUND: Preeclampsia and fetal growth restriction increase cardiopulmonary disease risk for affected offspring and occur more frequently at high-altitude (≥2500 m). Retrospective studies indicate that birth to a preeclampsia woman at high altitude increases the risk of pulmonary hypertension (PH) in later life. This prospective study asked whether preeclampsia with or without fetal growth restriction exaggerated fetal hypoxia and impaired angiogenesis in the fetal lung, leading to neonatal cardiopulmonary circulation abnormalities and neonatal or infantile PH. METHODS AND RESULTS: We studied 79 maternal-infant pairs (39 preeclampsia, 40 controls) in Bolivia (3600-4100 m). Cord blood erythropoietin, hemoglobin, and umbilical artery and venous blood gases were measured as indices of fetal hypoxia. Maternal and cord plasma levels of angiogenic (VEGF [vascular endothelial growth factor]) and antiangiogenic (sFlt1 [soluble fms-like tyrosine kinase]) factors were determined. Postnatal echocardiography (1 week and 6-9 months) assessed pulmonary hemodynamics and PH. Preeclampsia augmented fetal hypoxia and increased the risk of PH in the neonate but not later in infancy. Pulmonary abnormalities were confined to preeclampsia cases with fetal growth restriction. Maternal and fetal plasma sFlt1 levels were higher in preeclampsia than controls and positively associated with PH. CONCLUSIONS: The effect of preeclampsia with fetal growth restriction to increase fetal hypoxia and sFlt1 levels may impede normal development of the pulmonary circulation at high altitude, leading to adverse neonatal pulmonary vascular outcomes. Our observations highlight important temporal windows for the prevention of pulmonary vascular disease among babies born to highland residents or those with exaggerated hypoxia in utero or newborn life.