During recovery from exercise, dynamic changes in neural, and local factors induce immediate hyperemia (0–20 min after exercise) and sustained vasodilation (20–120 min after exercise) (Laughlin et al., 2012). Halliwill et al. (2013) proposed that sustained vasodilation after exercise may contribute to the growth and remodeling of microvasculature. Increased capillary supply improves the delivery of oxygenated blood to working muscles, and thus increases the arteriovenous oxygen differences by increasing the diffusion area within tissues. These changes lead to increased oxygen uptake and consequent improved performance in endurance exercise (Brodal et al., 1977). Therefore, establishing a method which can prolong or enhance sustained post-exercise vasodilation may be beneficial for endurance athletes who require maximal aerobic capacity.

Altitude training is a popular method used by competitive athletes, because hematological mechanisms (changes in red blood cell mass), and non-hematological mechanisms (such as angiogenesis, glucose transport, glycolysis, and PH regulation) of adaptation to hypoxia may enhance competitive performance (Gore et al., 2007; Girard et al., 2017). Additionally, combining exposure to hypoxia with exercise has been reported to improve O₂ transport and/or metabolism within muscles (Lundby et al., 2009), suggesting that exercise under such conditions may induce angiogenesis. If angiogenesis is in fact induced by post-exercise vasodilation, then exercise-induced vasodilation might be enhanced at higher altitudes. Indeed, inspiration of hypoxic gas has been shown to increase vascular conductance during submaximal exercise via the endothelial function-related pathway, as described by Casey et al. (2010), and enhance flow-mediated dilation (FMD) after submaximal exercise (Katayama et al., 2013) in young sedentary males. However, hemodynamics after intense (maximal and supramaximal) endurance exercise under conditions of hypobaric hypoxia have not been explored. It has been reported that maximal exercise under normoxic conditions causes a transient increase in reactive hyperemia (Schroeder et al., 2019), and that high-intensity interval training under hypoxic conditions improves maximal oxygen uptake and performance during repeated-sprint exercise (Brocherie et al., 2017). Studies on endurance athletes could have clinical implications for other athletes because the effects of exercise and altitude may differ between trained and sedentary individuals.

The accompanying negative effects of altitude training must be considered along with the training benefits. The incidence and severity of acute mountain sickness symptoms such as headaches, dizziness, fatigue, and restless sleep depend on the altitude reached and rate of ascent (Hackett et al., 1976). The hypoxic conditions in the studies mentioned above (Casey et al., 2010; Katayama et al., 2013) were relatively severe, at <80% arterial oxygen saturation (SpO₂); in terms of safety, studies in a milder hypoxic environment are important. To the best of our knowledge, there have been no investigations into the effects of exercise under mild hypoxic conditions on sustained post-exercise vasodilation.

We hypothesized that mild hypobaric hypoxia can enhance sustained post-exercise vasodilation in endurance athletes. To test this hypothesis, we evaluated the effects of artificial altitude conditions equivalent to 2,200 m above sea level on the systemic vascular resistance after maximal endurance exercise in young male runners. We chose 2,200 m because the arterial O₂ saturation reduced at this altitude may be sufficient to stimulate vasodilation after exercise, as indicated by a previous study which reported that 8 weeks of aerobic training under similar hypobaric hypoxic conditions improved FMD, and arterial stiffness in postmenopausal women (Nishiwaki et al., 2011).

We hypothesized that mild hypobaric hypoxia enhances sustained post-exercise vasodilation in endurance athletes. This is the first study to investigate the effects of mild hypoxia on vasodilation after intense endurance exercise. The differences in SBP, MBP, and TPR responses to exercise under the different conditions of this study suggest that the reduction in systemic vascular resistance after intensive endurance exercise persists longer after exercise in mild HH conditions despite the lower exercise volume.

Systemic vascular resistance is controlled by neural and local factors (Pescatello et al., 2004). Sympathetic activity is a neural factor that increases systemic vascular resistance. In general, sympathetic activity increases with short-term exposure to hypoxia via chemical receptors (Smith and Muenter, 2000). In the conditions of the present study, however, hypoxia-induced sympathetic vasoconstriction may have been overcome by compensatory vasodilation. With regards to local factors, hypoxia augments release of the endothelium-derived vasodilators adenosine (Leuenberger et al., 1999), prostaglandin (Messina et al., 1992), and nitric oxide (NO) (Casey et al., 2010). Hypoxia-induced expression of endothelial NO synthase mRNA (Shaul et al., 1995; Le Cras et al., 1998; Xiao et al., 2001) may be implicated in hypoxia-induced vascular responses because receptors for hypoxia-inducible factor, a transcriptional regulator, are present in the endothelial NO synthase promoter area (Coulet et al., 2003). However, brachial artery FMD, which represents an index of NO-mediated vasodilation, was not affected by hypoxia in the present study. Katayama et al. (2016) reported that reactive hyperemia in response to exercise was not enhanced in the inactive limb of subjects breathing a hypoxic gas mixture (12.0% fraction of inspired oxygen, FiO₂) compared to a normoxic gas mixture (21.0% FiO₂), although it was enhanced in the active limb (Katayama et al., 2013). We measured FMD in the upper arm, which was active, although secondary to the lower limbs. Effects of hypoxia on post-exercise FMD might have been identified if FMD had been measured in the arteries of the leg. On the other hand, it is possible that local factors other than NO contribute to the impact of hypoxia on TPR. A previous study showed that sustained post-exercise vasodilation is dependent on activation of the histamine H1 and H2 receptors (McCord and Halliwill, 2006). However, it remains unclear whether the histamine response is modified by hypoxia. Further studies are needed to understand the details of the mechanisms underlying the prolonged post-exercise decrease in systemic vascular resistance that was observed in HH conditions in this study.

Most of the subjects of previous studies on hypoxic vasodilation were sedentary young individuals (Casey et al., 2010; Katayama et al., 2013). In contrast, we showed that competitive runners exhibited sustained post-exercise decreases in systemic vascular resistance after exercise in mild HH conditions. The expected angiogenesis of the microvasculature, which may be related to post-exercise sustained vasodilation, is more important in such endurance athletes due to their requirement for increased aerobic capacity compared with sedentary individuals. In addition, HH conditions may be more beneficial than conditions of normobaric hypoxia for endurance-trained athletes who compete in high-speed running, because the reduced air density modifies the air resistance, and facilitates high-speed movements (Ward-Smith, 1984). However, normobaric hypoxia may have other benefits for endurance athletes (Millet et al., 2012).

Our findings could contribute to the development of a new training method for athletes. Furthermore, elderly or hypertensive subjects who need to improve their vascular function may benefit from hypoxic exercise. The combination of hypoxic stimuli and exercise improves several parameters of vascular function, including reduced blood pressure, which are pertinent for the reduction of cardiovascular risks (Millet et al., 2016). Therefore, we propose that altitude exercise has possible clinical applications to various populations, although further studies are needed for this potential to be realized. First, although we have demonstrated that the post-exercise reduction in SBP, MBP, and TPR persist for longer after exercise in HH conditions, we did not observe the recovery of baseline for these parameters. Future studies of post-exercise hemodynamics with increased observation periods could provide important insight. Second, the effects of hypoxia on vasculature depend on the hypoxic level, as indicated by the finding that mortality from stroke decreases with increasing altitude of the place of residence (12% per 1,000 m) (Faeh et al., 2009). The effects of low- and high-intensity hypoxia may differ with regards to the mechanisms involved in post-exercise vasodilation. Identifying the optimal altitude for enhancement of post-exercise vasodilation would be highly significant for athletes and clinicians.

The present study had some limitations. First, we examined only acute-vessel responses to a single bout of endurance exercise. A long-term intervention study is needed to ascertain whether the sustained vasodilation after exercise under conditions of hypoxia contributes to growth and remodeling of the microvasculature. Second, since we studied young male collegiate runners, we cannot generalize the present findings to the entire population. Third, the sample size was relatively small, and we found that some differences in measurements did not reach statistically significant level.

Our findings suggest that reductions in systemic vascular resistance induced by endurance exercise might persist longer under mild HH conditions (equivalent to 2,200 m above sea level), even when the absolute exercise volume is reduced, and compared with NN conditions (equivalent to sea level). Mild HH and post-exercise hemodynamics seem to have additive effects in young runners when compared with NN conditions.

This study was carried out in accordance with the recommendations of Ethical Guidelines for Medical and Health Research Involving Human Subjects, the Ministry of Education, Culture, Sports, Science and Technology of Japan with written informed consent from all subjects. All subjects gave written informed consent in accordance with the Declaration of Helsinki. The protocol was approved by the Ethics Committee of the Japan Institute of Sports Sciences.

YS contributed to the entire process of the work including the design of the study, acquisition, analysis, interpretation of the data, and writing of the manuscript. MN and KE contributed to the acquisition and interpretation of the data. TO contributed to the interpretation of data and the critical repeated revisions of the manuscript. All authors contributed to manuscript revision and have read 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.