(769.2) Multi-Omics Integration and the Development of Gestational High Altitude Induced Pulmonary Arterial Hypertension

Poster Board Number: E593

Eric Leslie (University of New Mexico), Ciprian Gheorghe (Loma Linda University School of Medicine), Alex Brito (Sechenov First Moscow State Medical University), Nana Anti (Loma Linda University School of Medicine), Breanna Jones (Loma Linda University School of Medicine), Lorelei Hughes (Loma Linda University School of Medicine), Kayla Sanchez (Loma Linda University School of Medicine), Chiranjib Dasgupta (Loma Linda University School of Medicine), Vanessa Lopez (Loma Linda University School of Medicine), Dmitry Grapov (CDS-Creative Data Solutions), Remy Bosviel (NIH West Coast Metabolomics Center), Ivana Blazenovic (NIH West Coast Metabolomics Center), Sam Murray (Loma Linda University School of Medicine), Michael Lee (Loma Linda University School of Medicine), Roberto Torres (Loma Linda University School of Medicine), Rucha Juarez (Loma Linda University School of Medicine), Steve Yellon (Loma Linda University School of Medicine), Lubo Zhang (Loma Linda University School of Medicine), Oliver Fiehn (NIH West Coast Metabolomics Center), John Newman (NIH West Coast Metabolomics Center), Michael La Frano (California Polytechnic State University), Sean Wilson (Loma Linda University School of Medicine)

High altitude (gt; 2500 meters) during pregnancy reduces oxygen delivery to the fetus (i.e., gestational hypoxia), causing abnormal fetal lung development. The pulmonary arteries become thicker and less functional, increasing the risk of pulmonary hypertension, which is a multiorgan disease that promotes right heart failure and under five-years mortality rate. Our previous work showed endoplasmic reticulum stress and metabolomic alterations in fetal sheep pulmonary arteries indicative of an unregulated inflammatory response after gestational hypoxia. To understand the relationships between inflammation, vascular remodeling, and pulmonary arterial hypertension development, we examined the omic links between the pulmonary arteries and plasma exosomes in fetal sheep exposed to high altitude (3801 meters) for the majority of the pregnancy (110+ days out of 138-141 days of pregnancy). Specifically, metabolomics and proteomic analyses from the pulmonary arteries and transcriptomic analysis of plasma exosomes were integrated from fetal sheep to understand the mechanisms driving this multiorgan disease. Sixteen miRNAs and 75 proteins were differentially expressed between normoxic and hypoxic samples. Gestational hypoxia resulted in significant changes in 90 metabolites in fetal pulmonary arteries. These results show exosomal microRNA are linked with pulmonary artery proteins and metabolites important to cell membrane composition which might explain their role in the facilitation of changes in vascular remodeling, inflammation, and cell signaling. Top canonical pathways noted in omics data integration were acute phase response signaling, atherosclerosis signaling, FXR/RXR activation, intrinsic prothrombin activation pathway, and LXR/RXR activation. This multi-omics study illustrates the intricacy of complex adaptations that occur in the fetal sheep lung in response to gestational hypoxia. 

Support or Funding Information

This work was supported by the National Science Foundation under Major Research Instrumentation, Division of Biological Infrastructure Grant No. 0923559 and National Institutes of Health Grants R03HD098477, the Loma Linda University School of Medicine, and a West Coast Metabolomics Center Pilot Project, R03HD098477 (SMW), Loma Linda University GCAT (SMW and CG), P01HD083132 and R01HL149608 (LZ) and U24DK097154 (OF). Additional support was provided by the USDA to JWN [Intramural Projects 2032-51530-022-00D, 2032-51530-025-00D]. The content is solely the responsibility of the authors and does not represent the official views of the NIH or USDA. The USDA is an equal opportunity employer and provider.