Long-term exposure to high-altitude hypoxic environments reduces blood pressure by inhibiting the renin-angiotensin system in rats

Delong Duo ¹ Junbo Zhu ¹ Mengyue Wang ¹ Xuejun Wang ² Ning Qu ³ Xiangyang Li ^1*

• ¹ Qinghai University, Xining, China
• ² Qinghai Red Cross Hospital, Xining, Qinghai Province, China
• ³ Qinghai Hospital of Traditional Chinese Medicine, Xining, Qinghai Province, China

Introduction: This study assesses the effects of chronic high-altitude hypoxia on blood pressure regulation in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats, focusing on cardiovascular remodelling, hemodynamic alterations, and renin-angiotensin system (RAS) modulation. Methods: Eight-week-old male SHR and WKY rats were divided into four groups: the SHR high-altitude hypoxia group (SHR-H), WKY high-altitude hypoxia group (WKY-H), SHR control group (SHR-C), and WKY control group (WKY-C). The hypoxia groups were exposed to 4,300 m (PaO₂: 12.5 kPa) for 10 weeks. Blood pressure was measured via non-invasive tail-cuff method, cardiac function via echocardiography, and right heart pressures via catheterization. Histopathological analysis included haematoxylin and eosin and Masson/Weigert staining for organ damage and vascular remodelling, whereas RAS components were assessed using immunohistochemistry. Results: The results showed that chronic hypoxia significantly reduced systolic blood pressure, diastolic blood pressure, and mean arterial pressure in SHR-H rats, but not in WKY-H rats. SHR-H rats showed a reduced ejection fraction, fractional shortening, systolic left ventricular anterior wall thickness, and diastolic left ventricular anterior wall thickness, increased left ventricular diastolic diameter, and left ventricular systolic diameter, whereas WKY-H showed only ejection fraction and fractional shortening decline. Both groups developed elevated mean pulmonary arterial pressure, right ventricular systolic pressure, and right ventricular end-diastolic pressure. SHR-H rats displayed aortic medial thinning, elastic fibre degradation, increased blood viscosity, and multi-organ damage (myocardial necrosis, pulmonary fibrosis), whereas WKY-H rats showed medial thinning and erythrocyte hyperplasia without fibrosis. Immunohistochemistry revealed suppression of the angiotensin-converting enzyme (ACE)-angiotensin II (Ang II)-angiotensin II type I (AT1) axis in SHR-H, whereas WKY-H exhibited reduced Ang I/II without ACE2 and Mas receptor (MasR) changes. Conclusion: Long-term hypoxic exposure at high-altitude reduces blood pressure in SHR rats, which may be attributed to a combination of cardiac functional compensation failure, vascular remodelling, and simultaneous inhibition of the ACE-Ang II-AT1R and ACE2-Ang1-7-MasR axes.