The physiological response of the pulmonary circulation to hypoxia is to increase pulmonary arteriolar resistance, resulting in elevated pulmonary artery pressure (ePAP) (1–6). Various degrees of increases in PAP at high altitudes have been reported in recent decades (3, 5–10). However, excessive ePAP in response to high-altitude hypoxia is a critical physiopathological factor in hypoxic adaptation leading to high-altitude pulmonary edema in the acute phase or high-altitude pulmonary hypertension (PH) in the long term (6, 11). In addition, the magnitude of hypoxic pulmonary vasoconstriction (HPV) in the high-altitude hypoxic environment is highly variable among humans, probably based on genetics and adaptive mechanisms (7, 12–14). Excessive HPV with ePAP may contribute to marked PH in sea-level residents with high-altitude exposure. Although a number of studies have investigated the prevalence and characteristics of high-altitude PH (HAPH) or isolated ePAP at high altitudes, few studies have reported the sea-level predictors of ePAP or risk factors for ePAP.

Previous studies assessed PAP in a limited number of populations by right heart catheterization (RHC), the recognized gold standard for PH at high altitudes (15, 16). However, at high altitudes, considering the reversibility of ePAP instead of HAPH in the acute phase after ameliorating hypoxia, invasive examination by RHC may be misused and be in contravention of the Declaration of Helsinki (2, 5, 6, 15, 16). Thus, it may be necessary to clarify the indications for RHC. As the technology for tools and tests has developed, rapid, non-invasive methods for evaluating ePAP have emerged, including echocardiography (15, 17). Echocardiography assessments of PAP have been widely used and have been recommended as the primary screening technology for PH at sea level by the American College of Cardiology Foundation (ACCF) (17). Non-invasive echocardiographic measurements are closely correlated with the gold standard (15). An echocardiography machine is also portable for high-altitude study and clinical practice.

In the past century, major studies in high-altitude medicine and physiology have focused on chronic high-altitude hypoxia-induced HAPH, which has been shown to be caused by hypoxia-induced pulmonary vascular remodeling (2, 5, 9). However, many reports have indicated an early phase onset of HAPH or increased PAP, even during only a few days of high-altitude exposure, which may be caused by hypoxia-induced pulmonary vasoconstriction (3, 6, 7). Although ePAP is not considered a type of acute mountain sickness and may recover to a normal level after a long period, it has been shown to limit activities of daily living (6). Additionally, ePAP has not been widely studied and is less understood, although it is reversible.

Numerous studies have focused on HAPH, and the alterations in PAP due to acute high-altitude exposure have not been thoroughly investigated (5, 8, 10, 14, 18). Acute high-altitude hypoxia-induced ePAP may be reversed after correcting hypoxia. During acute high-altitude exposure, PAP has been reported to significantly increase due to the hypoxic ventilatory response (HVR) and HPV (3, 4). We found that the increased mPAP decreased cardiopulmonary function and physical work capacity and even limited the activities of daily living of those unaccustomed to living at high altitudes (6). In recent decades, a reduction in the concentration of nitric oxide (NO) and an increase in the concentration of endothelin 1 (ET-1) have been shown to play pivotal roles in HAPH (19–21). Furthermore, prostaglandin E2 (PGE2) may also be involved in the development of HAPH, and two vascular regulatory factors with inverse roles, namely, Ang (1–7) and Ang II, have been shown to participate in systemic hypertension in low-altitude residents (22). However, their associations with PAP or HAPH are unknown, and the mechanisms underlying acute high-altitude hypoxic ePAP are not fully understood. There are also numerous other vascular regulatory factors that may contribute to the alterations in PAP due to high-altitude hypoxia that has not been studied in recent years.

Thus, we performed a field clinical trial based on a large population after acute high-altitude exposure to identify (1) the effect of acute high-altitude hypoxia exposure on PAP and (2) the baseline systemic blood risk factors for/predictors of increased PAP.

We first investigated the alterations in Ang (1–7) and Ang II from sea level to high altitude and identified that the baseline NO and Ang II concentrations are two independent predictors of ePAP. We found that the PAT decreased significantly after acute high-altitude exposure to 3,700 m within 24 h. Consequently, the mPAP increased significantly. We also found changes in hemodynamics and vascular regulatory factors. Furthermore, the sea-level baseline NO and Ang II concentrations are two independent predictors of ePAP after high-altitude exposure. Additionally, at high altitudes, we also found the associations of ET-1, NO, PEG2, Ang (1–7) and Ang II concentrations, and ePAP.

We found that the hemodynamics was enhanced by high-altitude exposure within 24 h. The HR increased significantly, which may be caused by hypoxia-induced sympathetic nerve activation (21, 23). However, the SV did not change significantly. These changes may be needed to supply sufficient blood and oxygen to the body under high-altitude hypoxic conditions. These alterations are compensatory responses to hypoxia. Furthermore, we discovered that in pulmonary hemodynamics, the PAT decreased sharply, while the mPAP increased significantly, which may also be compensatory responses. The enhanced hemodynamics was in accordance with previous studies and our reports.

The previous studies have indicated that systolic PAP calculated from tricuspid regurgitation and the mPAP calculated from the PAT are closely correlated (15, 17). However, their comparison has not been tested directly. In this study, we assessed PAP using the PAT instead of tricuspid regurgitation because not all the subjects suffered from tricuspid regurgitation.

Vascular regulation induced by hypoxia at high altitudes occurs by various mechanisms. First, vasoactive substances play critical roles in the vascular response to hypoxia. ET-1 levels showed a sharp increase within the first 24 h, while the strongest vasodilator, NO, displayed a dramatic reduction, which is consistent with previous studies (20, 21, 24). It is possible that hypoxia may constrict vessels by increasing the concentrations of vasoconstrictors and reducing the concentrations of vasodilators. However, regarding other regulatory factors, BK levels increased approximately 2-fold, while SP levels did not change significantly. These findings are similar to those of other reports on the effects of high-altitude exposure on BK and SP levels (25, 26). The changes in these vascular regulatory factors may be attributed to acute high-altitude stress.

It is well known that Ang II is one of the classic members of the renin-angiotensin-aldosterone system (RAAS), which participates in the development of hypertension. We found that Ang II levels rose significantly from sea level after acute high-altitude exposure, indicating that acute hypoxia may trigger the activation of the RAAS. Another study showed that angiotensin receptor blockers (ARBs) work with fewer effects at altitudes higher than 5,300 m, which may be attributed to the activation of the RAAS, including an increase in Ang II levels (27). Furthermore, ePAP populations have a higher level of Ang II both at sea level and high altitude (27).

In addition, we assessed another newly identified vascular regulator, Ang (1–7), which is produced from Ang I and Ang II. Ang (1–7) has been demonstrated to function in the dilation of blood vessels in an NO- and BK-dependent manner. Ang (1–7) may also play an inverse role to Ang II (27, 28). In contrast, both Ang (1–7) and Ang II are produced from Ang I; thus, the increase in Ang (1–7) may lead to a decrease in Ang II (29, 30). Thus, the balance between these factors after high-altitude hypoxia exposure may participate in the development of ePAP. This is the first report on the association between ePAP and Ang II or Ang (1–7).

Previous studies of hypoxia exposure have indicated that levels of constrictive factors increase significantly, while those of most vasodilators decrease significantly, resulting in vessel constriction, which causes an increase in blood pressure and increased velocities of blood flow and blood vessel resistance, including pulmonary arteries, thus leading to enhanced pulmonary hemodynamics (18, 23).

We further analyzed the associations between ePAP and hemodynamics. As discussed above, the hypoxia-induced constriction of blood vessels enhances hemodynamics. Although the HR increased significantly from sea level to high altitude in accordance with a previous study, neither the mPAP nor HAPH showed any associations with the HR. Furthermore, we did not find a correlation between ePAP and right heart function or left heart function. However, the mPAP was closely associated with the LAD, which may be caused by the interaction between the left heart and right heart (7).

In this study, we examined several commonly recognized vascular regulatory factors to identify the predictors of risk factors for ePAP. First, we investigated the strongest vasoconstrictor, ET-1, the concentration of which increased significantly after high-altitude hypoxia exposure. However, we did not find any associations or differences between mPAP or ePAP and the baseline ET-1 level. Previous studies have reported that ET-1 plays critical roles in PH and HAPH, as it is involved in the underlying mechanisms, including promoting the proliferation of both endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) as well as the constriction of the pulmonary artery due to EC dysfunction (31–33). However, the findings of this study were inconsistent with the results of several other studies, possibly due to the limited sample size in combination with the high-altitude exposure pattern.

Several vasodilators were also assessed in this study, including SP (a type of tachykinin and inflammatory factor), PGE2 (permeability), and 5-HT (emotion regulation), which may be significantly changed by high-altitude hypoxia. After high-altitude stress, the circulatory concentrations of the abovementioned vasodilators changed significantly, except for SP. These results were partly in accordance with previous studies. However, we did not find any associations with ePAP in either the correlation analysis or logistic regression.

In addition, we investigated the strongest vasodilator, NO, which has been shown to be effective for treating HAPH as well as to have a close association with HAPH. However, the predictive role of the baseline NO level at sea level in ePAP after acute exposure is unknown. In accordance with a previous report, we found that after high-altitude exposure, both the baseline and high-altitude NO concentrations were significantly associated with the mPAP. Furthermore, the baseline NO concentration at sea level also showed significant differences between the ePAP− and ePAP+ groups. We also identified that a lower baseline NO level is an independent predictor of ePAP.

Finally, the newly identified vascular regulator Ang (1–7) and the hypertension contributor Ang II were also investigated (16, 20, 27, 34). The baseline level of Ang II showed a significant association with ePAP at both altitudes, indicating its role in ePAP subjects and their susceptibility. However, Ang (1–7) at baseline showed no association with ePAP. After high-altitude exposure, Ang (1–7) was significantly lower in the ePAP subjects, showing that Ang (1–7) may be a protective factor against ePAP.

This cohort study was designed to identify the baseline risk factors for ePAP or predictors of ePAP resulting from high-altitude exposure. After correlation analysis and univariate and adjusted logistic analyses, we found that a lower baseline NO level and a higher baseline level of Ang II were predictors of ePAP and had not been previously identified. A previous study reported a decrease in exhaled nitric oxide on chronic intermittent hypoxia exposure in well-acclimatized mine workers. The above-mentioned literature investigated the effect of chronic hypoxia on the respiratory tract which may play a role in the acclimatization (35). Another study has shown that acute exposure to hypobaric hypoxia in the mountains due to the shortage of oxygen as a substrate for NO synthesis leads to a decrease in exhaled NO in HAPE-susceptible individuals. The exhaled nitric oxide may be a valuable index of health or diseases at high altitudes (36). However, we did not measure the exhaled nitric oxide level on acute exposure to high altitude. This should be improved in our future studies and should be combined with the respiratory functions at high altitudes.

Additionally, at high altitudes, the levels of ET-1, NO, PEG2, Ang (1–7), and Ang II as well as the LA were independently associated with ePAP, which may indicate that they are involved in the physiopathological mechanisms of ePAP. Specifically, Ang (1–7) and Ang II or their balance may contribute to the development of ePAP. Ang (1–7) and Ang II play different roles in smooth muscle cell proliferation, EC function maintenance, and systemic hypertension (16, 20, 27, 34). Furthermore, considering their competitive relations, their interactions and their roles in the underlying mechanisms of ePAP/HAPH should be given sufficient attention in future studies. In addition, ePAP/HAPH may be a process of high-altitude illness, which affects the daily work or life among the population at high altitudes. Thus, the predictors of ePAP or characteristics for ePAP may provide the prevention for high altitude illness.

The mPAP was closely associated with Ang II and NO levels. Baseline Ang II and NO concentrations at sea level were two independent predictors of ePAP after acute high-altitude exposure with opposite effects. Furthermore, Ang (1–7) and Ang II at high altitudes may contribute to the development of ePAP after acute high-altitude exposure.

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.

The studies involving human participants were reviewed and approved by the Ethics Committee of Xinqiao Hospital at the Second Clinic Medical College of the Third Military Medical University. The patients/participants provided their written informed consent to participate in this study.

X-HD and LH participated in the design of this study. X-HD and S-ZB drafted the manuscript, performed the statistical analysis, and performed the analysis of PAP-related measurements. LH reviewed and revised the manuscript critically for important intellectual content. R-SR performed the echocardiography examination. CZ and S-ZB collected the demographic data and blood examination data. The other laboratory measurements were performed by X-HD, S-ZB, and CZ. All authors contributed to the article and approved the submitted version.

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.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.