Hypertension induced by hypoxia at high altitude is one of the typical symptoms of high-altitude reactions (HARs). Emerging evidence indicates that endothelial abnormalities, including increases in angiotensin-2 (Ang-2) and endothelin-1 (ET-1), are closely associated with hypertension. Thus, low blood oxygen-induced endothelial dysfunction through acceleration of Ang-2 and ET-1 synthesis may alleviate HARs. In this study, we investigated the effects of hypoxia on rat blood pressure (BP) and endothelial injury. We found that BP increased by 10 mmHg after treatment with 10% O₂ (~5500 m above sea level) for 24 h. Consistently, serum Ang-2 and ET-1 levels were increased along with decreases in NO levels. In endothelial cells, angiotensin-1-converting enzyme (ACE) and ET-1 expression levels were upregulated. Interestingly, nuclear respiratory factor 1 (NRF1) levels were also upregulated, consistent with the changes in ACE and ET-1 levels. We further demonstrated that NRF1 transcriptionally activated ACE and ET-1 by directly binding to their promoter regions, suggesting that the endothelial cell dysfunction induced by hypoxia was due to NRF1-dependent upregulation of ACE and ET-1. Surprisingly, testosterone supplementation showed significant protective effects on BP, while castration induced even higher BPs in rats exposed to hypoxia. We further showed that physiological testosterone repressed NRF1 expression in vivo and in vitro and thereby reduced Ang-2 and ET-1 levels, which was dependent on hypoxia. In summary, we have identified that physiological testosterone protects against hypoxia-induced hypertension through inhibition of NRF1, which transcriptionally regulates ACE and ET-1 expression.

高原缺氧诱发的高血压是高原反应（HARs）的典型症状之一。新出现的证据表明，内皮异常，包括血管紧张素-2 (Ang-2) 和内皮素-1 (ET-1) 的增加，与高血压密切相关。因此，通过加速 Ang-2 和 ET-1 合成，低血氧诱导的内皮功能障碍可以缓解 HAR。在这项研究中，我们研究了缺氧对大鼠血压 (BP) 和内皮损伤的影响。我们发现用 10% O _{2治疗后 BP 增加了 10 mmHg}（海拔约 5500 米）24 小时。与此一致，血清 Ang-2 和 ET-1 水平随着 NO 水平的降低而升高。在内皮细胞中，血管紧张素-1 转换酶 (ACE) 和 ET-1 表达水平上调。有趣的是，核呼吸因子 1 (NRF1) 水平也上调，与 ACE 和 ET-1 水平的变化一致。我们进一步证明 NRF1 通过直接结合其启动子区域转录激活 ACE 和 ET-1，这表明缺氧诱导的内皮细胞功能障碍是由于 NRF1 依赖性上调 ACE 和 ET-1。令人惊讶的是，睾酮补充剂对 BP 显示出显着的保护作用，而去势可在暴露于缺氧的大鼠中诱导更高的 BPs。我们进一步表明生理睾酮在体内和体外抑制 NRF1 表达，从而降低依赖于缺氧的 Ang-2 和 ET-1 水平。总之，我们已经确定生理性睾酮通过抑制 NRF1 来防止缺氧引起的高血压，NRF1 转录调节 ACE 和 ET-1 的表达。