## 1 Introduction  
Erythrocyte aggregation is a critical hemorheological property that contributes to dynamically regulating blood flow and influencing oxygen delivery. Impaired rheological functions of erythrocytes lead to circulatory disorders, such as myocardial ischemia and infarction [1], cerebral infarction [2], and diabetes mellitus [3]. Erythrocyte aggregation occurs at low shear rates and depends on both cellular (intrinsic erythrocyte aggregability) and plasma fibrinogen-related erythrocyte adhesion factors (extrinsic factors) [4], as well as the disaggregating shear force generated by blood flow [3]. A great amount of evidence indicates that the aggregation tendency can be modified by several properties, such as erythrocyte aging in vivo [5], reactive oxygen species (ROS) [6], inflammatory status [7], or the blood hematocrit [8].  
Endurance exercise is an efficient and safe strategy to improve cardiopulmonary capacity. A number of studies have well established the effects of endurance training on hemorheological properties [9]. In patients with marked obesity or insulin resistance who receive therapeutic exercise training, plasma viscosity and hemorheology are mostly improved and reflect a change in plasma fibrinogen [10]. Altitude/hypoxic training appears to be more effective than sea-level/normoxic training for improving cardiopulmonary capacity [11]. However, exposure to a hypoxic environment may incur a progressive rigidity of erythrocytes [12] or even deteriorate antioxidative capacity [13]. Of clinical relevance, inappropriate hypoxia, such as severe sleep apnea, impairs rheological properties as well [12].  
Elevated erythropoietin (EPO) production in hypoxia is a key factor in the achievement of enhanced hematological variables. Its level depends on the duration of exposure and degree of hypoxia [14]. Hypoxic exercise markedly lowers the oxygen concentration or saturation of working organs by simultaneously decreasing oxygen supply and increasing oxygen demand to augment hypoxemia. Therefore, hypoxic exercise training may trigger hypoxia-inducible factor-1 (HIF-1)-mediated processes, then stimulate EPO secretion [15]. Despite an elevated plasma EPO level, the repeated, excessive exposure to ROS may further trigger erythosis or neocytosis, thereby counterbalancing erythropoiesis induced by EPO or accumulating stress reticulocytes [16].  
Our previous study demonstrated that hypoxic exercise training (HE) causes erythrocyte senescence and simultaneously promotes cryptic response to oxidative stress [13]. In addition, intermittent hypoxia exposure, acute exercise, or inflammation status promotes platelet aggregation [17] and also elevates the plasma fibrinogen concentration [14]. Therefore, excessive oxidative stress is caused by acute hypoxia exercise, which may trigger erythosis and lead to surface charge alteration, whereas chronic hypoxia exposure is speculated to enhance erythrocyte affinity with fibrinogen [18]. The effects of hypoxic exercise training on the erythrocyte aging process, cryptic response to oxidative stress, and aggregation properties remain unclear [19]. We hypothesize that hypoxic exercise training impairs erythrocyte rheological functions by raising affinity to fibrinogen and suppressing the negative charge via facilitating erythrocyte senescence and turnover rate.  
The aim of this study was to clarify the distinct effects of exercise training with or without hypoxia on erythrocyte aggregation, further providing a feasible strategy for developing an appropriate exercise regimen that improves cardiopulmonary fitness and minimizes the risk of hemorheological disorders. This study evaluated the following issues: (1) intrinsic aggregability, (2) fibrinogen binding probability and force, (3) mature erythrocyte and reticulocyte subfraction, and (4) erythrocyte senescence marker expression during a hypoxic exercise test (HET) in healthy sedentary men.