# Effect of Physical Exercise on the Release of Micorparticles with Angiogenic Potential
## 7 Angiogenesis Induced by Physical Exercise  
Physical activity has beneficial effects on human health [72; 73; 74; 75], and regular physical exercise improves health in both physiological and pathological conditions [76; 77; 78; 79]. Numerous evidence demonstrates the inverse relationship between regular exercise and cardiovascular diseases, hypertension, stroke, type 2 diabetes mellitus, metabolic syndrome, obesity, osteoporosis, and various types of cancer [76; 80; 81; 82; 83]. Depending on the type of physical exercise, we can observe different effects on the organism: endurance (or aerobic) exercise is characterized by a high number of muscular contractions, relative low load, and an important involvement of the cardiorespiratory system, whereas resistance exercise is represented by low number of muscular contraction but with relative higher loads and thus it relies mainly on the neuromuscular system [84]. These two types of exercise can be considered two extremes in a line, and between these two, numerous types of exercise exist, based on the modulation of the exercise variables (e.g., intensity, volume, density, rest). Each type of exercise can increase different responses and adaptions, triggering diverse cellular pathways.  
Cardiovascular endurance training is the strongest stimulus for exercise-induced angiogenesis; this results in an improved capillary to fiber ratio in the skeletal muscle to provide an enhanced blood flow and oxygen delivery to the exercising muscles [85; 86; 87; 88; 89]. Endurance exercise stimulatesthe angiogenesis activating several pathways (Figure 1). It induces an important reduction of the partial pressure of oxygen that leads to a local tissue hypoxia. This modification in oxygen levels decreases the hydroxylation of HIF-1 alpha trough the inhibition of prolyl hydroxylase domain enzymes (PHD); in this way, HIF-1 alpha become more stable and translocate into the nucleus, where forms an active complex with HIF-1 beta [90] and activates genes involved in angiogenesis such as VEGF [84]. Another key regulator of VEGF synthesis is the peroxisome proliferatorator-activated receptor gamma co-activator 1-alpha (PGC-1 alpha), which is modulated by aerobic exercise in several ways: intense endurance exercise produces an energy deficit and an increase of the AMP/ATP ratio that activate the AMP-activated protein kinase (AMPK) responsible for the PGC-1 alpha phosphorylation. Moreover, an acute bout of exercise increases the NAD+/NADH ratio that promotes the sirtuin (specifically SIRT1) activity and PGC-1 alpha deacetylation [91]. Finally, aerobic exercise affects also the estrogen-related receptor gamma (ERR gamma) that controls the skeletal muscle vascularization by modifying the VEGF expression [92].  
In the last years it was evidenced that physical exercise induces modification of the MPs release into the bloodstream [93]. These EVs carry various molecules important for the tissues' crosstalk during and post exercise [94; 95] and can be also a cargo of soluble factors involved in endothelial cell proliferation, migration, and adhesion. This results in the generation of new vessels in response to exercise.  
Figure 1: Representation of the main pathways activated in skeletal muscle in response to exercise. In addition to the canonical molecular pathways, aerobic exercise may affect the release of microparticles (MPs) that carry soluble factors involved in angiogenesis. AMP = adenosine monophosphate; ATP = adenosine triphosphate; NAD = nicotinamide adenine dinucleotide; NADH = reduced nicotinamide adenine dinucleotide; PGC-1\(\alpha\) = peroxisome proliferatorator-activated receptor gamma coactivator 1-alpha; HIF = hypoxia-inducible factor; VEGF = vascular endothelial growth factor; PDGF = platelet-derived growth factor.