Influence of Exercise or Physical Activity in the Angiogenesis Process: Integrative Review
Received Date: April 10, 2020; Published Date: April 23, 2020
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. The study data collection took place between February 20 and March 20, 2020. The electronic databases used to search the articles was PubMed (National Library of Medicine and National Institutes of Health). We used the keywords: angiogenesis, angiogenic effect, vascular endothelial growth factor (VEGF), physical activity, physical exercise, exercise and training, in the English languages, accompanied by the expression AND and selected through DeCS (Descriptors in Health Sciences). The performance of physical activity, (Figure 2), whether aerobic or resisted with load, promotes in the body an increase in pro-angiogenic factors such as: IL-6, Ang 1 and 2, VEGF, PDGF, FGF and stimulation of their receptors, being, respectively: IL -6Ra, TIE-2, VEGFR-1 and 2, PDGFR, FGFR. Higher levels of Adropine also encourage the expression of VEGFR-2. The activation of IL-6Ra, VEGFR-1 and 2 receptors elevates, together with increased expression of miR-126, a small fragment of non-coded RNA, the enzyme PI3k (Phosphoinositide 3-kinase). This increased enzyme induces the expression of protein Kinase B (Akt) which plays a fundamental role in cell metabolism via the mTOR pathway. We will then have the formation of MMP-2, MMP-9, VEGF, CD31 and HIF-1α, the latter being directly stimulated by the increase in NO. In this way, those responsible for proliferation, migration, survival and cell permeability will be present, necessary for improvements in the levels of angiogenesis to occur. It was possible to conclude that the physical activity induced in both experimental and human models favored the process of angiogenesis in organisms by increasing pro factors and decreasing anti-angiogenic factors, regardless of preexisting comorbidities and previous sedentary lifestyle.
Keywords: Physical activity; Exercise; Angiogenesis; Vascular Endothelial Growth Factor
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 . 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 formation of blood vessels from hemangioblasts that differentiate into mature blood and endothelial cells . Angiogenesis is the process of forming new blood vessels from a pre-existing vascular network, by capillary sprouting . Vasculogenesis ascends the heart and the first primitive vascular plexus within the embryo and in the surrounding membranes, considering that angiogenesis is responsible for the remodeling and expansion of this network. 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 [5-8]. However, physical inactivity is a risk factor for several pathological conditions, including obesity, hypertension, atherosclerosis and cancer [9-11]. Physical training is known to profoundly alter the morphology of blood vessels along the arterial tree [12-14]. 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 [15-18]. 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 .
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.
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 .
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. From these concepts, the guiding question was defined: what is the scientific evidence available in the literature on the relationship between physical activity and events related to the angiogenesis process. After formulating the question to be researched, a bibliographic survey was carried out on the PubMed platform. The survey of the study took place between February 20 and March 20, 2020. And the selection of texts proceeded with searches on the platform, using the filters available for texts published between 2010 and 2020. For the selection of publications, the following were adopted inclusion criteria: scientific articles, published in the English language, between 2010 and 2020, available online and free of charge in full. Articles with no abstract in the database or incomplete, editorials, letters to the editor, reflective studies, systematic or integrative literature reviews were excluded. After defining the guiding question, location and selection of articles, 74 publications potentially eligible to be included in this review were identified. After applying the inclusion and exclusion criteria, the sample consisted of 47 publications, the abstracts of 24 records were analyzed to see if they would meet the eligibility criteria and answer the question that guides this review, thus excluding 23 records and only 24 were analyzed in full to confirm eligibility for quantitative synthesis and data analysis according to the selection flowchart (Figure 1).
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) , 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 . 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 . 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 . 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 . 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 . 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 . 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 .
Table 1:List of articles that investigated the influence of physical activity on the angiogenesis process in experimental models.
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 . In this sense, aerobic and resistance exercise with load also promoted, in the study by Hassan and Kamal (2013) , 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 . 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 . 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 . In addition, the practice of exercise performed by mice with a gradual increase in intensity progressively increased the angiogenic factors VEGFR-2 (FLK-1) .
Likewise, obese and normal weight individuals, whether sedentary or not, were submitted to physical activity in the swimming modality. The results obtained by Gomes et al. (2017) , indicated an increase in pro-angiogenic factors in physically active individuals, this increase being higher in individuals with normal weight when compared to obese individuals. Analyzing the practice of physical exercises on a treadmill, performed by male rats to the detriment of sedentary mice, it can be concluded that those who exercised, obtained a significant increase in angiogenic factors when compared to those who did not practice .
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 . 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 .
Table 2:List of articles that investigated the influence of physical activity on the angiogenesis process in human trials.
Positive results regarding the induction of angiogenesis mediators were reported in the study by Van Pelt, et al. (2017) , in which regular physical exercises, including: physical maintenance on a treadmill and exercise bike, promoted changes in inflammation of macrophages in the subcutaneous tissue and increased levels of VEGFA, CD31, CD14 and IL-6. Walking as the physical activity of choice for 13 weeks reduces the inflammatory state and significantly improves serum angiogenic properties. A reduction in IL-8, TNF-α, Leptin, Resistin, Adiponectin and an increase in DHEA-S were evidenced .
On the other hand, when performing serial biopsies in young adults at rest, after cycling for 60 minutes, Hoier and Cols (2012) , evidenced despite the slight increase in TIE-2, TSP-1, Ang2, MMP-9 and VEGF, which would practically not influence the angiogenic potential of trained muscles. Regarding the practice of resistance exercises, Larkin and Cols (2012) , show that the acute restriction of blood flow in patients with muscle microlesions, who performed knee extensions with load showed an increase in mRNA related to skeletal muscle angiogenesis in response to changes in hemoglobin concentration in skeletal muscle. In addition, resisted physical activity with weight, either with high load and little repetition, or with little load and high repetition, promoted an increase in muscle mass and also in angiogenic factors . In individuals undergoing resistance physical exercise, there is a transient increase in pro-angiogenic markers and an increase in cell proliferation in vitro. However, the overlapping of vibrations to that same exercise results in decreased proliferation of cells by decreasing the circulating VEGF, and may therefore not be beneficial for triggering angiogenesis-inducing signaling pathways .
The performance of physical activity, (Figure 2), whether aerobic or resisted with load, promotes in the body an increase in pro-angiogenic factors such as: IL-6, Ang 1 and 2, VEGF, PDGF, FGF and stimulation of their receptors, being, respectively: IL -6Ra, TIE-2, VEGFR-1 and 2, PDGFR, FGFR. Higher levels of Adropine also encourage the expression of VEGFR-2. The activation of IL- 6Ra, VEGFR-1 and 2 receptors elevates, together with increased expression of miR-126, a small fragment of non-coded RNA, the enzyme PI3k (Phosphoinositide 3-kinase). This increased enzyme induces the expression of protein Kinase B (Akt) which plays a fundamental role in cell metabolism via the mTOR pathway. We will then have the formation of MMP-2, MMP-9, VEGF, CD31 and HIF-1α, the latter being directly stimulated by the increase in NO. In this way, those responsible for proliferation, migration, survival and cell permeability will be present, necessary for improvements in the levels of angiogenesis to occur.
Physical activity was of fundamental importance in inducing angiogenesis. Through these studies, it was possible to notice that both in experimental models and in human beings, foods or comorbidities, the practice of physical exercises, either resistant to loads or aerobics, considerably improved the levels of vascular evaluation, clinical factors, expression enzyme and its receptors. In addition, anti-angiogenic factors apply at the highest levels in those who remain sedentary, corroborating the idea that the practice of physical activity is of paramount importance for neovascular formation, or that it may possibly cause a determining factor in the quality of life and health of individuals.
Conflict of Interest
No conflict of interest.
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