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 post-natal 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 analyses 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.

中文翻译：

---

使用模拟高海拔暴露的小鼠模型对发育性心肺适应慢性缺氧的转录组修饰。

驱动对慢性高海拔 (HA) 暴露的适应性发育反应的机制尚不完全清楚。我们开发了一种新的大鼠模型，模仿人类对 HA 的心肺适应状况，从受孕开始，跨越子宫内和出生后的时间范围。我们评估了肺生长和心肺结构和功能，并进行了转录组分析，以确定促进发育适应慢性缺氧的机制。为了生成模型，将繁殖对的 Sprague-Dawley 大鼠暴露在低压缺氧环境中（相当于海拔 9,000 英尺）。交配、怀孕和分娩发生在缺氧条件下。在产后六周收集后代的结构和功能数据。RNAseq 在右心室 (RV) 和肺组织上进行。在室内空气 (RA) 条件下，年龄匹配的繁殖对和后代作为对照。缺氧大鼠表现出显着较低的体重和较高的血细胞比容水平、肺泡体积、肺扩散能力、RV 质量、RV 收缩压以及肺动脉重塑增加。RNAseq 分析揭示了缺氧大鼠肺和 RV 中的多个差异表达基因。虽然与 RA 对照相比，缺氧肺和 RV 之间存在相当大的相似性，但确定了肺或 RV 特有的几个上游调节器。我们注意到免疫下调模式以及免疫和激素介质的调节模式，类似于肺动脉高压患者的基因组。总之，我们开发了一种新的慢性缺氧暴露小鼠模型，该模型展示了类似于人类适应的功能和结构表型。我们确定了表明适应慢性 HA 的潜在机制的转录组学改变。