High Altitude Hypoxia Induces Cellular Immaturity of Pulmonary Arteries in the Fetal Lamb: Assessment of Protein Biomarkers

Abstract

Pulmonary Arterial Hypertension (PAH) in newborns can be mediated by intrauterine hypoxia and which can cause significant aberrations on vascular structure and function. Previous evidence suggests that long term hypoxic stress can induce phenotypic modifications to various vascular beds, including those of the lung. We are now seeking to interrogate the influence of intrauterine hypoxia on pulmonary vascular phenotypes and to test the hypothesis that intrauterine hypoxia causes the vasculature to shift from a mature to an immature phenotype. This was evaluated by examining protein expression using proteomic analyses on pulmonary arteries isolated from near term fetal lambs that were exposed to intrauterine high altitude hypoxia (3801 m) for the latter 110+ days of pregnancy or those gestated near sea level. Protein networks were created via Ingenuity Pathway Analysis (IPA) and Search Tool for the Retrieval of Interacting Genes/Proteins (STRING). Intrauterine hypoxia caused a number of significant changes including reducing the expression of smooth muscle myosin, fibronectin, and collagen along with upregulation of proteins involved in nucleotide synthesis, mitosis/cell proliferation, as well as cell adhesion and migration. The observed changes are consistent with a hypoxia‐induced phenotypic shift towards cells being more synthetic, proliferative, and migratory. Such findings provide insight into the mechanistic underpinnings related to the development of pulmonary hypertension due to gestational hypoxia. This work opens new avenues of investigation to determine common signaling pathways affected by intrauterine hypoxia with the aim of discovering the fundamental mechanisms driving hypoxia‐induced remodeling and senescence.Support or Funding InformationSupported in part by NIH grants HD083132 (LZ), HD098477 (SMW), RA was a Apprenticeship Bridge to College summer research fellow through the LLU Center for Health Disparities Research with funding from P20MD006988 (M. DeLeon) from the National Institute of Health Disparities and Minority Health of the National Institutes of Health.