Plasma exosome derived MiR221 as a driver of long term hypoxia induced aberrations in pulmonary arterial phenotype in fetal sheep

• Published in: Physiology (Bethesda, Md.) Vol. 38; no. S1
• Main Authors: Sierra, Julio, Gheorghe, Ciprian, Leslie, Eric, Dasgupta, Chiranjib, Brito, Alex, Zhang, Lubo, Newman, John, La Frano, Michael, Fiehn, Oliver, Wilson, Sean
• Format: Journal Article
• Language: English
• Published: 01.05.2023
• ISSN: 1548-9213; 1548-9221
• DOI: 10.1152/physiol.2023.38.S1.5796248

Abstract only Pregnancy at high altitude (> 2500 meters) reduces oxygenation to the fetus (i.e., gestational hypoxia). The low oxygenation causes abnormal fetal lung development, with pulmonary arteries becoming thicker and dysfunctional. Associated with these structural and functional aberrations there is an increased risk of pulmonary hypertension, an intractable disease that increases infant mortality. Our previous work using a gestational high-altitude sheep model shows that the fetus has pulmonary vascular remodeling, heart dysfunction, endoplasmic reticulum stress, metabolomic alterations and inflammatory responses. To better understand the relationships between inflammation, vascular remodeling, and the development of pulmonary arterial hypertension, we used a multi-omic approach examining pulmonary arteries and plasma exosomes in fetal sheep exposed to high altitude (3801 meters) for most of pregnancy (110+ days out of 138-141 days of pregnancy). We sought to understand the role of exosome derived microRNA as drivers of the malformations in fetal pulmonary vascular development using ingenuity pathway analysis of exosomal microRNA in combination with pulmonary arterial metabolites and proteins. Transcriptomic analysis showed that miR221 was upregulated in plasma exosomes. Pathway analysis identified a miR221 - AKT dependent signaling axis as a candidate pathway that downregulates pulmonary arterial expression of smooth muscle myosin heavy chain 11 and multiple collagen isoforms. Although the pathway analysis needs validation, the predictions show that changes in plasma exosomes are likely coordinated to discrete alterations in proteins coupled to smooth muscle phenotype and arterial wall structure. These effects are predicted to be linked to pulmonary arterial aberrations associated with the development of pulmonary hypertension in response to gestational hypoxia. This work was supported by the National Institutes of Health Grants R03HD098477, a West Coast Metabolomics Center Pilot Project, NIH R01HL155295, R01HL149608, R03HD098477, P01HD083132, R01HL149608, and U24DK097154. 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. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.