Influence of Exercise or Physical Activity in the Angiogenesis Process: Integrative Review

Lucas Cecin de Deus Spirandelli1, Mateus Borges Soares1, Otávio Cortes Alves1, Vítor Brandão Veloso1, Pedro Teixeira Meireles1, Thiago Mantello Bianco2, Bruno Belmonte Martinelli Gomes2, Eduardo Elias Vieira de Carvalho3, Ana Karina Marques Salge4, George Kemil Abdalla5 and Douglas Reis Abdalla1,5* 1Medicine Course, University of Uberaba, Uberaba, MG, Brazil 2Biomedicine, Serrana State Hospital, Serrana, SP, Brazil 3Professor, Department of Applied Physical Therapy Federal University of Triângulo Mineiro, Uberaba, MG, Brazil 4Professor, Faculty of Nursing, Federal University of Goiás, Goiânia, GO, Brazil 5Professor, Health Sciences, Faculty of Human Talents, Uberaba, MG, Brazil


Introduction
The word "angiogenesis" was derived from the Greek where "angio" means blood vessel and "genesis" means production or birth, together they refer to the generation of blood vessel within the body. Historically, the term angiogenesis was first used to describe the growth of endothelial shoots from pre-existing postcapillary veins. Over time, this term has been used to denote the process of growth and remodeling of the primitive network of a vascular complex [1]. The vascular system is responsible for the supply of nutrients and oxygen in an organism. New blood vessel formation or neovascularization is divided into two components like vasculogenesis and angiogenesis. The vasculogenesis process is the During this process, mature endothelial cells are divided and incorporated into new capillaries. The signaling of vascular endothelial growth factors (VEGF) is necessary for the complete performance of vasculogenesis and angiogenesis [2,4].
The health benefits of regular physical activity are present in several chronic diseases, including cardiovascular disease, diabetes, hypertension and cancer [5][6][7][8]. However, physical inactivity is a risk factor for several pathological conditions, including obesity, hypertension, atherosclerosis and cancer [9][10][11]. Physical training is known to profoundly alter the morphology of blood vessels along the arterial tree [12][13][14]. Exercise provides increases related to the quantity (angiogenesis) and the diameter (arteriogenesis) of the arterial blood vessels in the skeletal muscle and in the myocardium.
These changes in the architecture of the vascular tree are probably associated with functional changes and improved blood flow to the organ [15][16][17][18]. Changes in vascular morphology induced by physical exercise in healthy individuals [15,16] are extremely dependent on the size of the initial vessel. A greater number of vessels in response to training, angiogenesis, appears to occur on the level of very small capillaries and arterioles (<40 μm in diameter), but not in large arteries. The increase in capillary density occurs just after the beginning of the exercise and is transient. A similar pattern was observed in very small arterioles (<20 μm in diameter) and slightly in larger arterioles (20-40 μm in diameter) an increase in the number was also observed [19].
The molecular mechanisms underlying exercise-induced angiogenesis are not fully understood. It has been suggested that growth factors such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF) and angiopoietins (ANG) as well as their corresponding receptors are involved. In addition, the proteases necessary for the degradation of the capillary basement membrane such as matrix metalloproteinases (MMPs), urokinase, tissue plasminogen activator probably contribute to the mechanism of the emergence of angiogenesis [16,20,21]. Interestingly, some of these proteases appear to allow and/or facilitate the mobilization of endothelial progenitor cells (EPCs) from the bone marrow.
It has become apparent that exercise can increase the number of circulating EPCs in animals and humans, and these cells are known to have a large capacity for neovascularization, a process that appears to be critically dependent on the protease cathepsin L [22,23]. In order to understand the relationships of the influence of physical activity in the angiogenesis process, this review aims to recruit in the last ten years the evidence on this topic.

Methodology
In the present study, an integrative review was conducted, which consists of research that allows the evaluation, synthesis and knowledge about a phenomenon from evidence, aiming to produce an overview of complex concepts, theories or relevant health problems from studies pre-existing, enabling the intervention proposal [24,25]. For the selection of articles, 6 methodological steps were carried out, namely: 1. elaboration of the guiding question or research hypothesis, that is, the problem was identified, the search engine and the keywords or keywords were presented; 2. establishment of the inclusion and exclusion criteria of the articles to be selected to compose the sample; 3. exploratory reading of the titles and abstracts of the articles for pre-selection; 4. analytical reading of the articles in order to compile, analyze and categorize the information; 5. interpretation of results. 6. synthesis followed by the presentation of the identified results, which permeate the guiding question [26]. Therefore, in this study it was decided to search for the concepts: angiogenesis, angiogenic effect, vascular endothelial growth factor (VEGF), physical activity, physical exercise, exercise and training.

Result and Discussion
The proposed review aimed to associate the practice of physical activity and angiogenic parameters, such as VEGF synthesis, expression of its receptors (VEGFR), as well as the expression of angiogenesis inducing molecules and involved in the quantification of microvascular density (CD31), as well as the synthesis of chemical mediators involved in this process. Thus, we divided the reviewed studies into two groups, namely: studies with experimental models and studies involving human beings. Table 1 lists the studies with experimental models of physical activity and angiogenic study. Thus, Lee and Cols (2018) [27], report that the performance of voluntary wheel exercises performed by mice for 6 weeks resulted in an increase in angiogenic factors. As well as, moderate intensity exercises performed by mice, during 8 weeks, increased the gene expression of angiogenic factors and decreased insulin resistance [28]. In addition, in the performance of physical activity performed by elderly mice, for 10 weeks, an increase in VEGF, an increase in BFR was observed, occurring a cardiac physiological remodeling corresponding to the demand [29]. The treadmill practice performed by mice is correlated to the increased expression of angiogenic factors, both in healthy animals and in animals with previous comorbidities [30]. Likewise, there was an improvement in the levels of cardiac markers correlated with physical activity performed on a treadmill by male mice at moderate intensity, for 8 weeks [31]. The practice of aerobic exercises performed by male mice, for 15 minutes/day for 8 weeks, is directly related to an improvement in cardiac angiogenesis and in the intramuscular capillary density [32]. Still, the practice of AET performed by male mice, which consists of swimming sessions of 60 minutes, 5 times a week, for 10 weeks, proved to be effective in vascular remodeling, being an important therapeutic target for the treatment of several cardiovascular diseases [33]. Individuals who performed physical exercise in swimming mode, at different intensities, obtained an increase in angiogenic factors, some of them (VGEF-B, MEF-2, MMP-2) with greater proportional increases in intensity and, on the other hand, ANGPT-1 and HDAC4 showed more satisfactory results at moderate exercise intensity [34]. Table 1: List of articles that investigated the influence of physical activity on the angiogenesis process in experimental models. VEGF and PFK ↑PFK These data demonstrate a vital role for myocyte VEGF at the start of the complex series of events necessary for exercise-induced skeletal muscle angiogenesis and provide additional evidence that skeletal muscle capillarity is one of the main factors contributing to overall exercise performance.

↑VEGF
Finally, rats with heart disease undergoing physical training, high intensity interval (HIIT) and continuous rhythm (CET), presented a decrease in myocardial fibrosis related to the aging process, in addition to increasing the amount of molecules linked to angiogenesis in the heart and in the endothelial tissue. Being that HIIT training induced a greater increase in VEGF [35]. In this sense, aerobic and resistance exercise with load also promoted, in the study by Hassan and Kamal (2013) [36], improvement in cardiac performance, hemodynamics and angiogenesis, related to the VEGF marker. The practice of physical exercise on a 4% inclined treadmill, for 1 hour, 5 times a week, for 8 weeks, in female mice, being diabetic and obese, proved to be effective in increasing angiogenic levels [37]. With the practice of physical activity performed on a treadmill by male rats with varying intensity (from mild to moderate), an improvement in cardiac remodeling initiated by CAT is observed [38]. In addition, it was found that performing a 17m / min intensity mat in male rats, from 10 to 50 minutes / day, for 10 weeks, decreased angio-static factors and increased angiogenic factors [39]. In addition, the practice of exercise performed by mice with a gradual increase in intensity progressively increased the angiogenic factors VEGFR-2 (FLK-1) [40]. factors when compared to those who did not practice [42]. Table 2 summarizes the studies involving human beings, in which the practice of physical activity with the use of an exercise bike, caused an increase in cytokines and angiogenesis and biogenesis factors in skeletal muscle cells [43]. Aerobic physical activity performed for 12 weeks promoted an increase in muscle capillarity, an increase in VEGF and VEGFR, an increase in HIF-α and α-tubulin. However, protein supplementation was not effective in changing these parameters, but the practice of physical activity [44]. In summary, data show that exercise leads to transient increases in circulating proangiogenic markers and, in addition, the proliferation of endothelial cells in vitro is increased by serum factors obtained acutely after exercise. However, superposition of vibrations to resistance exercise decreases the concentrations of VEGF in circulation after exercise, which supposedly results in reduced endothelial cell proliferation in vitro, that is, the superposition of a vibration stimulus to resistance exercise may not be beneficial for the triggering of angiogenic inducing signaling pathways in skeletal muscle.  The performance of physical activity, (Figure 2