Transcriptomic Modifications in Developmental Cardiopulmonary Adaptations to Chronic Hypoxia Using a Murine Model of Simulated High Altitude Exposure

Mechanisms driving adaptive developmental responses to chronic high altitude (HA) exposure are incompletely known. We developed a novel rat model mimicking the human condition of cardiopulmonary adaptation to HA starting at conception and spanning the in utero and early life timeframe. We assessed lung growth and cardiopulmonary structure and function, and performed transcriptome analyses to identify mechanisms facilitating developmental adaptations to chronic hypoxia. To generate the model, breeding pairs of Sprague-Dawley rats were exposed to hypobaric hypoxia (equivalent to 9,000 feet elevation). Mating, pregnancy and delivery occurred in hypoxic conditions. Six weeks postpartum, structural and functional data were collected in the offspring. RNAseq was performed on right ventricle (RV) and lung tissue. Age-matched breeding pairs and offspring under room air (RA) conditions served as controls. Hypoxic rats exhibited significantly lower body weights and higher hematocrit levels, alveolar volumes, pulmonary diffusion capacities, RV mass, RV systolic pressure as well as increased pulmonary artery remodeling. RNAseq revealed multiple differentially expressed genes in lungs and RVs from hypoxic rats. While there was considerable similarity between hypoxic lungs and RVs compared to RA controls, several upstream regulators unique to lung or RV were identified. We noted a pattern of immune down-regulation and regulation patterns of immune and hormonal mediators similar to the genome from patients with pulmonary arterial hypertension. In summary, we developed a novel murine model of chronic hypoxia exposure that demonstrates functional and structural phenotypes similar to human adaptation. We identified transcriptomic alterations that suggest potential mechanisms for adaptation to chronic HA. Age matched 7-week old male or female Sprague Dawley rats (200-225 g) were acclimated to either room air or hypobaric for three weeks until they achieved the appropriate breeding age of 10 weeks. At 10 weeks, each mating pair was placed together in a standard cage for mating in their respective room air or hypoxic environments. A hypobaric hypoxia chamber, depressurized to an equivalent of an inspired oxygen fraction of 15%, was used to simulate a 9,000 feet HA environment. Males were removed from the cages once the female was visibly pregnant and females delivered naturally at term. Pups were weaned at 21 days and physiologic experiments and animal sacrifice with tissue harvest occurred at 6 weeks of age. Animals exposed to in utero and postnatal room air are denoted RA-RA and animals exposed in utero and postnatal hypoxia are denoted H-H. Lung and heart right ventricle (RV) tissues were flash frozen in liquid nitrogen and stored at -80C until RNA preparation. Animals from 2 separate litters at RA-RA of H-H were used approximately equal numbers of males and females. RNA-seq analysis on 29 rat lung samples (15 RA-RA; 14 H-H) and 26 RV samples (11 RA-RA; 14 H-H) was completed.