3.3.1. Hypoxia

As a major effect, exercises under BFR reduce oxygen concentration, leading to hypoxia and, consequently, increase the number of metabolic products [58]. Mostly named as such are blood lactate and muscle cell lactate [58]. The blood lactate concentrations are significantly increased following low-intensity resistance training under ischemic conditions, such as BFR as compared with a performed exercise protocol under normal conditions [59]. Thereby, a pressure gradient is built which favors the flow of blood into the muscle fibers in the intracellular space [28]. The result is an increased cell volume which leads to altered cell structure and ultimately drives anabolic signal pathways. This cellular swelling supports the increased protein synthesis in many different cell types including muscle fibers [28,60]. Cell swelling can indicate muscle growth through the proliferation and fusion of satellite cells [61].

Tissue hypoxia can also trigger an increase in localized and systemic hormone synthesis. These effectors are likely to lead to an increased release of anabolic growth factors [58]. In training with BFR, the growth hormone levels are up to 290 times greater as compared with a matched control group that trained without vascular occlusion [59]. Consequently, training under BFR leads to skeletal muscle remodeling in connection with anabolic growth factors expression. Resistance training under BFR seems to stimulate 1.8 times greater muscle recruitment than volume-matched non-BFR strength trainings [59]. As a consequence thereof, muscle protein synthesis could be stimulated [62].

#### 3.3.2. Vascular Adaption

The application of BFR also influences the vascular system supply by promoting post-exercise blood flow, oxygenation, and arteriogenesis. Here, an increase of angiogenetic and arteriogenetic factors after BFR trainings, such as vascular endothelial growth factor and hypoxia inducible factor 1 alpha [63], are commonly described. Additionally, an increase in protein biosynthesis, higher concentrations of heat shock proteins (HSP), and the enzyme nitric oxide synthase (NOS) are present in blood serum after BFR training [64]. Nitric oxide (NO) is an important cellular signaling molecule which is produced in high levels in muscle by neuronal NOS. The production of NO is connected with the mammalian target of rapamycin (mTOR) activation and, subsequently, with protein synthesis [65]. In practice, the role of NO in vasodilatation under ischemic conditions is increased as compared with normoxic conditions, which results in an upregulation of endothelial NOS (eNOS) [66]. BFR training evokes similar mechanisms of vascular adaption and promotes arteriogenesis, such as increased fluid shear stress as a consequence of a slowly progressing vascular stenosis does. One known process following arteriogenesis is "pruning", which means that the number of collateral arteries decreases after a certain level of arteriogenesis is reached and fluid shear stress decreases by self-limitation due to a diminishing pressure gradient. Similar phenomena occur after successful revascularization; collateral arteries shrink or disappear as the main blood flow is directed through the vascular reconstruction, e.g., a bypass. In this situation, the e ffect of BFR on vascular adaption remains unclear. With respect to the risk of mechanical damage to the reconstruction or its occlusion caused by reduced blood flow during the compression period, BFR is considered to be a potential therapeutic option in chronic PAD patients under conservative treatment. Furthermore, after revascularization, the potential benefit of BFR regarding vascular adaption is questionable.
