3.2.1. Neovascularization

Beyond that, physical training has the potential to promote neovascularizationin hypoxic andischemic tissues, such as in the myocardium or peripheral limbs [40,41]. Two forms of neovascularization can be distinguished, angiogenesis and arteriogenesis. Angiogenesis is driven by hypoxia and is usually characterized by the sprouting of newly formed capillaries [42]. Arteriogenesis is defined as the growth of functional collateral arteries from pre-existing arterio-arteriolar anastomoses [43]. The latter, arteriogenesis, can be induced by exercise, in humans [44–46], rats [46], and in mice [25,47]. A fluid shear stress-associated

transient receptor potential cation channel, subfamily V, member 4 (trpv4) [48], turned out to be upregulated transiently after endurance training [46].

#### 3.2.2. Fluid Shear Stress

The driving force of arteriogenesis is the altered fluid shear stress (FSS) in preformed collateral arteries. It is triggered by increased blood flow [49]. Although this FSS can be impacted by exercise training, the initiation of vascular remodeling and diameter growth [50] remains incomplete. The FSS, as well as the induction of related molecules, returned to baseline values already 6 h post exercise. A more frequent exercise to chronically increase FSS was proposed to be required for sufficient arteriogenesis to compensate for a peripheral occlusion [46].

Several mechano-sensors and transducers that convey the FSS message during collateral remodeling have been proposed. These include ion channels [51], the glycocalyx layer of endothelial cells (ECs) [52], and nitric oxide (NO) [53]. Recently, microRNAs (miRNAs) have also been proposed as potential factors to control the response of vascular cells to hemodynamic stress [54]. In addition, miRNAs can be secreted, and thereby can contribute to intercellular communication [55]. Hence, miRNAs have also been linked to FSS-induced arteriogenesis [56].

In addition, structural and functional adaptations of the vasculature can also be induced by exercise training in humans. These changes have been shown in young endurance athletes who presented larger diameters of the main conduit arteries of their trained limbs as compared with matched legs of untrained controls [44–46,57].

#### *3.3. Evidence of BFR Exercise E*ff*ects*

Although not finally delineated, some identical, some comparable, and some completely different vascular mechanisms for the effects of blood flow restriction exercises are known. The mechanisms of BFR exercise are based on the combination of two primary factors, metabolic and mechanical stress. These two factors act synergistically to signal a number of secondary mechanisms such as tissue hypoxia, metabolite formation, and cellular swelling, which, afterwards, stimulate autocrine and paracrine signaling pathways, ultimately leading to protein synthesis, type II muscle fiber recruitment, local and systemic anabolic hormone synthesis, and stimulation of myogenic stem cells [28].
