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High-altitude exposure results in hypobaric hypoxia, which affects organisms by activating several mechanisms at the physiological, cellular, and molecular levels and triggering the development of several pathologies. One such pathology is high-altitude pulmonary hypertension (HAPH), which is initiated through hypoxic pulmonary vasoconstriction to distribute blood to more adequately ventilated areas of the lungs. Importantly, all layers of the pulmonary artery (adventitia, smooth muscle, and endothelium) contribute to or are involved in the development of HAPH. However, the principal action sites of HAPH are pulmonary artery smooth muscle cells (PASMCs), which interact with several extracellular and intracellular molecules and participate in mechanisms leading to proliferation, apoptosis, and fibrosis. This review summarizes the alterations in molecular pathways related to oxidative stress, inflammation, kinase activation, and other processes that occur in PASMCs during pulmonary hypertension under hypobaric hypoxia and proposes updates to pharmacological treatments to mitigate the pathological changes in PASMCs under such conditions. In general, PASMCs exposed to hypobaric hypoxia undergo oxidative stress mediated by Nox4, inflammation mediated by increases in interleukin-6 levels and inflammatory cell infiltration, and activation of the protein kinase ERK1/2, which lead to the proliferation of PASMCs and contribute to the development of hypobaric hypoxia-induced pulmonary hypertension., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Siques, Pena, Brito and El Alam.)

Background: Prolonged exposure to altitude-associated chronic hypoxia (CH) may cause high-altitude pulmonary hypertension (HAPH). Chronic intermittent hypobaric hypoxia (CIH) occurs in individuals who commute between sea level and high altitude. CIH is associated with repetitive acute hypoxic acclimatization and conveys the long-term risk of HAPH. As nitric oxide (NO) regulates pulmonary vascular tone and asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NO synthesis, we investigated whether ADMA concentration at sea level predicts HAPH among Chilean frontiers personnel exposed to 6 months of CIH. Methods: In this prospective study, 123 healthy army draftees were subjected to CIH (5 days at 3,550 m, 2 days at sea level) for 6 months. In 100 study participants with complete data, ADMA, symmetric dimethylarginine (SDMA), L-arginine, arterial oxygen saturation (SaO 2 ), systemic blood pressure, and hematocrit were assessed at months 0 (sea level), 1, 4, and 6. Acclimatization to altitude was determined using the Lake Louise Score (LLS) and the presence of acute mountain sickness (AMS). Echocardiography was performed after 6 months of CIH in 43 individuals with either good ( n  = 23) or poor ( n  = 20) acclimatization. Results: SaO 2 acutely decreased at altitude and plateaued at 90% thereafter. ADMA increased and SDMA decreased during the study course. The incidence of AMS and the LLS was high after the first ascent (53 and 3.1 ± 2.4) and at 1 month of CIH (47 and 3.0 ± 2.6), but decreased to 20 and 1.4 ± 2.0 at month 6 (both p  < 0.001). Eighteen participants (42%) showed a mean pulmonary arterial pressure (mPAP) >25 mm Hg, out of which 9 (21%) were classified as HAPH (mPAP ≥ 30 mm Hg). ADMA at sea level was significantly associated with mPAP at high altitude in month 6 ( R  = 0.413; p  = 0.007). In ROC analysis, a cutoff for baseline ADMA of 0.665 μmol/L was determined to predict HAPH (mPAP > 30 mm Hg) with a sensitivity of 100% and a specificity of 63.6%. Conclusions: ADMA concentration increases during CIH. ADMA at sea level is an independent predictive biomarker of HAPH. SDMA concentration decreases during CIH and shows no association with HAPH. Our data support a role of impaired NO-mediated pulmonary vasodilation in the pathogenesis of HAPH.

An increasing number of people are living or working at high altitudes (hypobaric hypoxia) and therefore suffering several physiological, biochemical, and molecular changes. Pulmonary vasculature is one of the main and first responses to hypoxia. These responses imply hypoxic pulmonary vasoconstriction (HPV), remodeling, and eventually pulmonary hypertension (PH). These events occur according to the type and extension of the exposure. There is also increasing evidence that these changes in the pulmonary vascular bed could be mainly attributed to a homeostatic imbalance as a result of increased levels of reactive oxygen species (ROS). The increase in ROS production during hypobaric hypoxia has been attributed to an enhanced activity and expression of nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase), though there is some dispute about which subunit is involved. This enzymatic complex may be directly induced by hypoxia-inducible factor-1α (HIF-1α). ROS has been found to be related to several pathways, cells, enzymes, and molecules in hypoxic pulmonary vasculature responses, from HPV to inflammation, and structural changes, such as remodeling and, ultimately, PH. Therefore, we performed a comprehensive review of the current evidence on the role of ROS in the development of pulmonary vasculature changes under hypoxic conditions, with a focus on hypobaric hypoxia. This review provides information supporting the role of oxidative stress (mainly ROS) in the pulmonary vasculature's responses under hypobaric hypoxia and depicting possible future therapeutics or research targets. NADPH oxidase-produced oxidative stress is highlighted as a major source of ROS. Moreover, new molecules, such as asymmetric dimethylarginine, and critical inflammatory cells as fibroblasts, could be also involved. Several controversies remain regarding the role of ROS and the mechanisms involved in hypoxic responses that need to be elucidated.

Background: In chronic hypoxia (CH) and short-term chronic intermittent hypoxia (CIH) exposure, glycemia and insulin levels decrease and insulin sensitivity increases, which can be explained by changes in glucose transport at skeletal muscles involving GLUT1, GLUT4, Akt, and AMPK, as well as GLUT4 translocation to cell membranes. However, during long-term CIH, there is no information regarding whether these changes occur similarly or differently than in other types of hypoxia exposure. This study evaluated the levels of AMPK and Akt and the location of GLUT4 in the soleus muscles of lean rats exposed to long-term CIH, CH, and normoxia (NX) and compared the findings. Methods: Thirty male adult rats were randomly assigned to three groups: a NX (760 Torr) group ( n = 10), a CIH group (2 days hypoxia/2 days NX; n = 10) and a CH group ( n = 10). Rats were exposed to hypoxia for 30 days in a hypobaric chamber set at 428 Torr (4,600 m). Feeding (10 g daily) and fasting times were accurately controlled. Measurements included food intake (every 4 days), weight, hematocrit, hemoglobin, glycemia, serum insulin (by ELISA), and insulin sensitivity at days 0 and 30. GLUT1, GLUT4, AMPK levels and Akt activation in rat soleus muscles were determined by western blot. GLUT4 translocation was measured with confocal microscopy at day 30. Results: (1) Weight loss and increases in hematocrit and hemoglobin were found in both hypoxic groups ( p < 0.05). (2) A moderate decrease in glycemia and plasma insulin was found. (3) Insulin sensitivity was greater in the CIH group ( p < 0.05). (4) There were no changes in GLUT1, GLUT4 levels or in Akt activation. (5) The level of activated AMPK was increased only in the CIH group ( p < 0.05). (6) Increased GLUT4 translocation to the plasma membrane of soleus muscle cells was observed in the CIH group ( p < 0.05). Conclusion: In lean rats experiencing long-term CIH, glycemia and insulin levels decrease and insulin sensitivity increases. Interestingly, there is no increase of GLUT1 or GLUT4 levels or in Akt activation. Therefore, cellular regulation of glucose seems to primarily involve GLUT4 translocation to the cell membrane in response to hypoxia-mediated AMPK activation.