Vascular dysfunction in obesity: Beneficial effects of aerobic exercise training in animal models

Abstract

Cardiovascular disease (CVD) is the leading cause of mortality in the world and several risk factors for developing CVD have been pointed out, including obesity and physical inactivity. Endothelial dysfunction as a consequence of metabolic and inflammatory disorders plays an important role in the onset of vascular complications in obesity. In addition, it is well established that aerobic exercises promote beneficial effects on CVD by increasing nitric oxide (NO) production or its bioavailability in human and experimental models. The interest in exercise studies increased significantly, with promising results. Considering the importance of this field, the purpose of this mini-review is to summarize the animal studies that investigated the physiological mechanisms of vascular dysfunction in obesity and how aerobic exercise training influenced these alterations.

Keywords
aerobic exercise training; vascular dysfunction; obesity

Introduction

Obesity is a chronic disease with rapid progression and deleterious effects of associated diseases, thus it is undoubtedly one of the major public health challenges in the world. In addition, obesity contributes to the origin of secondary pathologies as well as: type 2 diabetes, hypertension, cardiovascular disease, cancer and neurodegenerative diseases¹. In the world, nearly 2 billion adults are overweight and, of these, more than half a billion are obese².

It is believed that the fundamental cause of weight gain and obesity is the imbalance between calories consumed and expended. Globally, there has been an increase in energy food (especially high fat) intake and an increase in physical inactivity due to the increasingly sedentary nature of many forms of work². Obesity is generally defined as an excess of body fat with the most commonly used anthropometric index being the body mass index (BMI) expressed in kilograms per square meter (kg/m²). There are other additional anthropometric measurements to establish the diagnosis of obesity such as waist/hip and skin folds¹.

Evidence shows that the sedentary lifestyle is the fourth largest risk factor for global deaths by secondary disease, being the biggest risk factor for the development of obesity². In fact, several studies have shown that regular physical exercise promotes cardiovascular benefits and physically active patients have increased longevity associated with reductions in morbidity and mortality².

Animal models are considered an important tool in basic science to study the vascular complications associated with obesity. The studies involving induction of obesity in animal models are useful for research due to their great similarity with the genesis and metabolic responses derived from weight gain/obesity in humans³.

Considering the practice of exercises has been widely discussed by various groups of researchers, it is necessary to properly describe the protocols of aerobic physical training with animals. In animal models, studies also observed reduced body weight, visceral obesity, and plasma glucose, as well as beneficial effects in cardiovascular parameters in obese rats and mice subjected to aerobic exercise training⁴. The aim of this mini-review is to summarize and integrate animal studies on the physiological mechanisms of vascular dysfunction in obesity and how they are influenced by chronic aerobic exercise training (Figure 1). Special attention will be taken to describe the protocols of physical exercise on the treadmill, including fitness training and strength analysis of the effectiveness of physical training in rodent models of obesity.

Figure 1
Chronic effects of aerobic exercise training on vascular dysfunction in obese animals.

Vascular Dysfunction in Obesity

Normal blood vessels have a structure consisting of three layers: tunica intima (endothelial cells), tunica media (smooth muscle cells) and tunica adventitia (extracellular matrix). Endothelial cells are responsible for the synthesis, metabolism and release of a large variety of mediators that regulate platelet and leukocyte activity, vascular tone, vascular permeability and the metabolism of endogenous and exogenous substances. The integrity of the endothelial cells is of fundamental importance in the maintenance and control of the cardiovascular system.

The influence of the endothelium in vascular tone is modulated by the synthesis and release of vasoconstriction (endothelin-1, prostaglandins, tromboxane A₂ - TXA₂, angiotensin II and the reactive oxygen species - ROS) and vasodilator substances (nitric oxide - NO, prostacyclin - PGI2 and endothelium-derived hyperpolarizing factors - EDHF). NO requires special attention, because of its important role in regulatory functions. In the regulation of vascular tone, NO has a significant vasodilator function, being able to spread easily between biological membranes⁵.

The nitric oxide enzymes (NOS), expressed in various tissues of the body, catalyze the oxidation of L-arginine in the presence of nicotinamide-adenine-dinucleotide phosphate (NADPH) in NO and L-citruline. In mammals, NO can be generated by three different isoforms of the NO synthase enzyme: neuronal NOS (nNOS or NOS I), inducible NOS (iNOS or NOS II), and endothelial NOS (eNOS or NOS III). All isoforms of NOS use flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN), and (6R-) -5,6,7,8-tetrahydro-L-biopterin (BH4) as cofactors. Endothelial NOS (eNOS) is mostly expressed in endothelial cells, which are very sensitive to the chemical stimulation of agonists such as bradykinin, acetylcholine, histamine, and adenosine triphosphate, among others. However, the best established stimulus is shear stress (mechanical stimulation of blood flow); its activation is mediated by the phosphorylation of the enzyme and it does not produce sustained increases in intracellular Ca²⁺, but still induces a long-lasting release of NO⁵.

Endothelial dysfunction (ED) is characterized by an imbalance between endothelium-derived relaxing and contracting factors, and is mostly associated with lower production and/or bioavailability of NO by endothelial cells³. ED as a consequence of metabolic and inflammatory disorders plays an important role in the initiation of vascular complications in obesity⁶, and it is the hallmark of obesity associated with erectile dysfunction, coronary artery disease and peripheral artery disease⁷,⁸. Previous studies have demonstrated an impairment of relaxant responses in the aorta, mesenteric⁹, femoral, and coronary arteries¹⁰ in experimental models of obesity, that were associated with diminished NO release. The impaired vascular function and an increased vascular oxidative stress observed in obesity were associated with increased levels of inflammatory adipocytokines such as leptin, and tumor necrosis factor alpha - TNF-α, as well as decreased levels of anti-inflammatory adipocytokines such as adiponectin¹¹.

Considering the interaction between pro-inflammatory mediators and vascular diseases in obesity, many studies demonstrated that increased levels of TNF-α, free fatty acids (FFA), leptin and resistin result in endothelial dysfunction¹¹. The physiological levels of leptin boost sympathetic nervous activity with increases in blood pressure and heart rate while its action on vascular tissues promotes NO release causing endothelium-dependent dilatation¹². However, this vasodilation effect induced by leptin is impaired in obese animals when hyperleptinemia is observed¹³. Also in the vascular tissue, either eNOS protein expression or NO bioavailability is reduced in the presence of TNF-α ¹⁴. On the other hand, adiponectin exerts vasculoprotective effects through a number of ways which includes increased NO production and/or its bioavailability due to enhanced eNOS activity or suppression of superoxide generation¹⁵. Moreover, the involvement of adiponectin in the regulation of TNF-α, affecting the coronary and aortic endothelium function, has been demonstrated¹⁶. It has been shown that there is an imbalance between the release of inflammatory and anti-inflammatory adipocytokines in obesity, and that it contributes for vascular oxidative stress¹⁷. This alteration is involved in the increased production of ROS such as superoxide anions (O₂ ^-), and its reaction with endothelial-derived NO reduces its bioavailability and leads to a highly unstable molecule, peroxynitrite (ONOO-). The damage in cells and tissues by ROS has been associated with the development of endothelial dysfunction, and consequently with cardiovascular diseases¹⁸. There are many studies that associate obesity and its oxidative and inflammatory disorders with vascular dysfunction, however the mechanisms involved are complex and not fully understood¹⁹. Therefore, studies involving obese animal models are important to elucidate and develop new approaches in this field, specially the involvement of obesity with cardiovascular diseases.

Physical Exercise and Aerobic Protocols in Animal Models

According to the Centers for Disease Control and Prevention (CDC), physical activity is defined as any bodily movement produced by the contraction of skeletal muscles that increases energy expenditure above the basal level. It generally refers to the subset of physical activities that enhance health. In turn, physical exercises are defined as a subcategory of physical activity that is planned, structured, repetitive, and purposive in the sense that it has the improvement or maintenance of one or more components of physical fitness as objective²⁰. On the other hand, physical inactivity is defined as physical activity levels lower than those required for optimal health and prevention of premature death, and functional capacity is the ability of a cell, organ, system, or body to maintain homeostasis within their narrow limits of survival in response to a specified stress²¹. It is well established that regular exercise not only enhances functional capacity but also brings about beneficial health outcomes²². Physical exercise leads to a variety of morphological and functional adaptations, which are known as the chronic effects of exercise²³.

Specifically, cardiorespiratory endurance or aerobic endurance is the ability of the whole body to sustain prolonged and rhythmic exercise²⁴. This type of adaptation involves an increase in the capacity of the muscles for aerobic metabolism with an increase in endurance and is found in its most highly developed form in the muscles of competitive athletes, such as long-distance runners, long-distance cross-country skiers, bicyclists, and swimmers. It is well established that endurance exercises involving large muscle groups are recommended for the maintenance or improvement of cardiovascular fitness²⁵. Considering the cardiovascular benefits of exercise have been attributed to aerobic exercise training, in this review we will focus on this type of exercise training.

The intensity of exercise could determine the degree of benefit to the cardiovascular system. Two tests of cardiorespiratory endurance - submaximal and maximal - appear in the literature. The test of submaximal (cardiorespiratory) endurance capacity is more closely related to actual competitive endurance performance and is likely determined by both the individual’s maximum oxygen consumption (VO₂max) and his or her lactate threshold. Maximal cardiorespiratory endurance capacity (aerobic power - VO₂peak) is defined as the highest rate of oxygen consumption attainable during maximal or exhaustive exercise²⁴. Well-controlled training studies in animal models are important, as they form the basis for translational research.

In rats and mice, accurate training intensity may be obtained by directly measuring the maximum oxygen consumption (VO₂max). For animal studies to mimic human standards for maximal cardiovascular endurance tests a determination of the VO₂max or VO₂peak may be obtained, as previously described²⁶. This approach, however, is time consuming and expensive, especially in comprehensive and long-lasting studies. Therefore, several other methods have been proposed to estimate exercise intensity without directly measuring the VO₂max. Heart rate increases linearly with power output and VO₂ both in humans⁶ and rats⁷. In humans, this method is easy to use through a number of commercial systems. In rats and mice, control by heart rate is more challenging, as monitoring requires implantation of transducers that impose a significant extra weight, especially in mice. Controlling training intensity by critical velocity⁸, and lactate threshold has also been proposed²⁷. The lactate threshold normally changes during a period of regular training, and frequent assessments are necessary for it to be used as a means of controlling the training stimulus⁶. In addition, frequent blood sampling is likely to affect the performance because of increased stress levels and reduced hemoglobin. Moreover, a correlation between the VO₂max and maximal running speed in rats and mice has been established. A previous study demonstrated that maximal running speed may be used both as a tool to adjust training intensity and to estimate the VO₂max at low and moderate intensity exercise training²⁶. Thus, this method may be a great way to control the intensity of physical exercise training in animal models.

Also, voluntary wheel running is used to assess physical performance and endurance (as an endurance and fitness test, which generally lasts less than 7 days) and to model exercise training as a way to enhance health in rodents, especially mice. Wheel running is a voluntary activity in contrast to other experimental exercise models, which rely on aversive stimuli to force active movement. This protocol consists of allowing mice to run freely on the wheel placed inside a standard cage. Each wheel is connected to a computerized activity monitoring system that provides a detailed analysis of voluntary wheel running for individual mice. Thus, rotations, frequency and rate of running can be captured via a software program for data storage and analysis for various time periods. Factors such as mouse strain, gender, age, and individual motivation, which affect running activity, must be considered in the design of experiments using voluntary wheel running²⁸. The advantage of voluntary running models is that animals are allowed to exercise at their own initiative, in terms of frequency, length and intensity of training. Voluntary exercise avoids some of the stressful factors related to forced training²⁹. Self-administered exercise may also be convenient for researchers, because it requires less supervision time²⁶. A disadvantage is the variability in the amount and intensity of the running performed by the mice on the wheels³⁰. The ability to control the dose of physical activity in terms of duration, frequency and intensity is therefore lost. Therefore, the question is whether the intensity of voluntary wheel running would provide the same protective benefits as 1 hour/day of controlled/forced exercise training. Mice run most intensely during the first several hours of the beginning of the active dark cycle, and it has been shown that voluntary wheel running for one hour a day five days a week generates physiological responses in mice in the long term³¹. However, more studies are needed to assess the health benefits of voluntary wheel running in mice, particularly in chronic disease models.

Chronic Effects of Aerobic Exercise Training on Vascular Dysfunction in Obesity

The association between obesity and physical inactivity is the most important risk factor for the development of cardiovascular diseases (CVD). Actually, physical inactivity is now regarded as one of the most prevalent cardiovascular risk factors². Numerous studies, confirmed by meta-analyses, indicate that exercise training reduces cardiovascular mortality and cardiovascular events³², particularly stroke, coronary heart disease, heart failure, and atherosclerosis³³. Moreover, exercise training is an effective therapeutic strategy for patients with peripheral arterial diseases, coronary heart disease, heart failure, atherosclerosis, and hypertension³². Specifically for the endothelial function, the time course of endothelial adaptation following acute and regular exercise in rats was demonstrated. They found that a single bout of exercise improves endothelium-dependent dilation for about 2 days, with peak effect after 12-24 h, and regular exercise further improves adaptation and promotes an approximately fourfold increase in the sensitivity to acetylcholine, which slowly returns to sedentary levels within a week of detraining³⁴.

The cardiovascular benefits of exercise have been frequently attributed to the reduction of many classical cardiovascular risk factors including blood lipids, high blood pressure, obesity, glucose, and type 2 diabetes as well as novel risk factors such as inflammation, and oxidative stress³²,³⁵. In the endothelial cells one of the most important molecular consequences of exercise training is the increase of vascular NO concentration. NO is responsible for vasodilation, which results in the lowering of peripheral resistance. The eNOS is up-regulated by an increase in flow-mediated shear stress associated with physical exercise due to a complex pattern of intracellular regulation like acetylation³⁶ phosphorylation³⁷ and translocation to the caveolae³⁸. It is now clearly documented that exercise or increased shear stress up-regulates eNOS activity in animal models³⁹. Besides the cardiovascular benefits of exercise training associated with a variety of cellular and molecular alterations including up-regulation of eNOS, an increase in the expression and/or activity of antioxidant enzymes, as well as a decrease in pro-oxidant enzyme systems have been demonstrated in animal models⁴⁰. The antioxidant defense systems consist of enzymes such as superoxide dismutase (SOD), catalase and glutathione peroxidase. These enzymes are scavengers of ROS resulting in an increase of NO bioavailability to the vascular smooth muscle and enhancement of endothelium-dependent vasodilatation⁹. However, it should be noted that exercise intensity seems to be a crucial variable in this response. A recent study evaluated the impact of exercise training on vascular gene expression profiles, using a transcriptome-wide RNA-Seq analysis in obese rats⁴¹. In particular, the analysis was performed on the soleus and gastrocnemius muscle feed arteries (SFA and GFA, respectively) and aortic endothelial cell-enriched samples from obese Otsuka Long-Evans Tokushima Fatty (OLETF) rats that underwent an endurance exercise training program (EndEx) or interval sprint training program (IST). They found that the number of genes which had their expression altered in response to both EndEx and IST was greater in the SFA compared with the GFA. Considering the fact that exercise produces greater relative increases in blood flow in the gastrocnemius muscle compared with the soleus muscle, these data suggest an interesting disassociation between the magnitude of exercise-induced vascular transcriptional changes and the magnitude of exercise-induced blood flow stimulus to which the arteries are exposed. They suggested that the signals produced by bouts of exercise that result in altered gene expression are not totally driven by hemodynamic forces associated with increased blood flow, suggesting that other signals produced by exercise may also be involved⁴¹. Thus, it is still unclear which mechanisms explain the beneficial effects of exercise in vascular cells.

Therefore, well-controlled training studies in animal models are important, as they form the basis for translational research. Considering the increased number of studies which investigate the effects of exercise training in pathological conditions, such as cardiovascular diseases and obesity, in recent years, it is important to know which methodologies are employed to study exercise or exercise training, and also if the exercise protocols were properly described by the authors. In this review we focused on animal models of obesity studies that investigated the effects of aerobic exercise training on the cardiovascular system, which were summarized in Table 1.

Table 1
Chronic effects of aerobic exercise training on cardiovascular system in obese animals: summary of studies.

References	Obesity Animal Models	AerobicExerciseProtocols	Resultson Cardiovascular System
Xiang L, et al. 2005 (42)	Obese Zucker Rats (OZR)	Treadmill (24 m/min) for 4-5 wk, (10-day acclimation period).	Obese Trained vsObese Sedentary rats -No difference in MAP; -Improved functional hyperemia and endothelial-dependent vasodilation in the spinotrapezius muscle.
De Moraes C, et al. 2008(9)	Male Wistar rats, high-caloric diet	Treadmill (70-80% VO2max), 1h/day, 5 days/wk for 12 wk.	Obese Trained vsObese Sedentary rats -No difference in NOx- levels; -Improved relaxation responses to acetylcholine in aortic and mesenteric rings; -Increased protein expression of CuZn-SOD in aorta and mesenteric arteries.
Sebai M, et al. 2011 (43)	Obese Zucker Rats (OZR)	Treadmill (24 m/min), 30 min/day, 5 days/wk for 6 wk.	Obese Trained vsObese Sedentary rats -Increased VO2max and workload; -Improved functional vasodilation in spinotrapezius and cremaster muscles.
Touati S, et al. 2011(44)	Male Sprague-Dawley rats, high-fat diet for 12 wk.	Treadmill (27 m/min), 60 min/day, 5 days/wk for 12 wk.	Obese Trained vsObese Sedentary rats -Decreased SAP and atherogenic index; -Improved endothelium-dependent relaxation to acetylcholine and insulin in aorta; -Increased to contents of aortic p-Akt at Serin473 and peNOS at Serin1177.
Barbosa VA, et al. 2012 (45)	Male Wistar rats, high fat-diet for 8 wk	Treadmill (1.0 km/h), 50 min/day, 5 days/wk for 8 wk.	Obese Trained vs Obese Sedentary rats -Decreased TBARS and superoxide in myocardial tissue; -Decreased TBARS, superoxide and carbonyl content in aorta; -Increased CuZn-SOD, CAT and GPx activities in myocardial and aorta.
Barretti DL, et al. 2012 (46)	ObeseZuckerRats (OZR)	Swimming sessions (1h/day, 5 days/wk, for 10 wk), wearing caudal dumbbells weighing 5% of their body weight.	Obese Trained vsObese Sedentary rats -No difference in the systemic ACE activity, resting heart rate and cardiac function; -Prevented increase in cardiac hypertrophy, cardiac ACE activity, Ang II and AT2 receptor; -Increased cardiac protein expression and activity of ACE2.
Mostarda C, et al. 2012 (47)	Male Wistar rats, overload of D-fructose (100 g/l) in drinking water for 10 wk	Treadmill (50-70% of the maximum running speed), 1h/day, 5 days/wk for 10 wk.	Obese Trained vs Obese Sedentary rats -Improvement in SAP, DAP, MAP, and diastolic function; -No difference in HR, and systolic function.
Moraes-Silva IC, et al. 2013 (48)	Male Wistar rats overload of D-fructose (100 g/l) in drinking water for 10 wk	Treadmill (50 -70% maximal running speed, 0.6 -1.3 km/h, 0% inclination), 1h/day, 5 days/wk for 10 wk.	Obese Trained vs Obese Sedentary rats -Improvement in SAP, DAP, MAP, HRV, SAPV, RMSSD, TR and BR; -No difference in HR.
Boa BC, et al. 2014 (49)	Male hamsters, high-fat chow starting on the 21st day of birth, for 12 wk.	Treadmill (50-70% of VO2max), 1h/day, 5days/wk for 8 wk.	Obese Trained vsObese Sedentary rats -Decreased MAP and HR; -Improved endothelial-dependent vasodilation in microcirculatory and the macromolecular permeability after ischemia/reperfusion in three 2ndto 3rdorder arterioles; -Increased eNOS protein expression in thoracic aorta.
Oharomari LK, et al. 2014 (50)	Male Wistar rats, highly palatable diet for 11 wk	Treadmill (60% maximal running speed), 1h/day, 5 days/wk for 7 wk.	Obese Trained vs Obese Sedentary rats -Improved relaxation response in aorta; -Increased protein expression of Ec-SOD, CuZn-SOD and reduced gp91phoxin aorta; -Decreased superoxide formation in aorta.
Pieri BL, et al. 2014 (51)	Diet-induced obesity (DIO) Wistar rats	Treadmill 50-min/day, 5 days/wk, velocity of 1.0 km/h for 8 wk.	Obese Trained vs Obese Sedentary rats -Increased p-P38MAPK, REDD1, and 14-3-3 protein levels in the myocardium of trained obese rats.
Touati S, et al. 2015 (52)	Male Sprague-Dawleyrats, high-fat diet for 12 wk.	Treadmill (27 m/min),60 min/day, 5 days/wk for 12 wk.	Obese Trained vsObese Sedentary rats -Decreased NADPH oxidase activity in aorta; -No difference in Nox1 and Nox2 expression in aorta. -Decreased protein expression of Nox4, p47phox translocation, VCAM-1, pERK 1/2 (Thr202/Tyr204) and pJNK/SAPK (Thr183/Tyr185) in aorta; -Increased CuZn-SOD protein expression in aorta.

• ^Note
  MAP: mean arterial pressure; SAP: systolic arterial pressure; DAP: diastolic arterial pressure; HR: heart rate; VO₂max: maximum oxygen consumption; NOx^-: nitrite/nitrate concentrations; CuZn-SOD: CuZn superoxide dismutase; Ec-SOD: extracellular superoxide dismutase; pAkt: phosphor protein kinase B; peNOS: phosphor endothelial nitric oxide synthase; TBARS: thiobarbituric acid-reactive substances; CAT: catalase; GPx: glutathione peroxidase; ACE: angiotensin I-converting enzyme; Ang II: angiotensin II; AT2: angiotensin II receptor; ACE2: angiotensin II-converting enzyme; HRV: heart rate variability; SAPV: systolic arterial pressure variability; RMSSD: root mean square successive difference; TR: tachycardia; BR: bradycardia; gp91^phox: subunit of NADPH oxidase complex; p-P38MAPK: phosphor P38 mitogen-activated protein kinase; REDD1: regulated in development and DNA damage responses 1; Nox 1: NADPH oxidase subunit enzyme 1; Nox 2: NADPH oxidase subunit enzyme 2; Nox 4: NADPH oxidase subunit enzyme 4; p47^phox: cytosolic subunit of NADPH oxidase complex; VCAM-1: vascular cell adhesion molecule-1; pERK 1/2: phosphor extracellular signal-regulated kinase; pJNK: phosphor c-Jun N-terminal kinase; SAPK: stress-activated protein kinase.

Conclusion

The association between obesity and physical inactivity is the most important risk factor for the development of cardiovascular diseases. Endothelial dysfunction as a consequence of metabolic and inflammatory disorders plays an important role in the initiation of vascular complications in obesity. On the other hand, many studies have shown the importance and effectiveness of exercise training in the prevention and treatment of cardiovascular disease in obesity. However, it is still unclear which mechanisms explain the beneficial effect of exercise in vascular cells. Therefore, well-controlled training studies in animal models are important, as they form the basis for translational research.

In summary, animal models of aerobic exercise training against obesity show promising benefits to the cardiovascular system. We found that most studies investigating the effects of aerobic exercise training on the cardiovascular system in animal models of obesity were concerned with the exercise training protocol used and also have been reported properly by the authors.

Acknowledgement

This work was supported in part by the Conselho Nacional de Desenvolvimento.Científico e Tecnológico - CNPq and the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES

References

• ¹
  Besnard P. Lipids and obesity: Also a matter of taste? Rev Endocr Metab Disord [Internet]. Reviews in Endocrine and Metabolic Disorders. 2016; May 10 Available from: http://dx.doi.org/10.1007/s11154-016-9355-2
  » http://dx.doi.org/10.1007/s11154-016-9355-2
• ²
  Word Health Organization. Global recommendations on physical activity for heathy. Word Health Organization, Geneva, out. 2010.
• ³
  Tschöp M, Heiman HL. Rodent obesity models: an overview. Exp Clin Endocrinol & Diabetes. 2001;109:307-319.
• ⁴
  Pons S, Martin V, Portal L, Zini R, Morin D. Regular treadmill exercise restores cardio protective signaling pathways in obese mice independently from improvement in associated co-morbidities. J Mol Cell Cardiol. 2013;54:82-89.
• ⁵
  Forstermann U, Sessa WC. Nitric oxide synthase: regulation and function. Eur Heart J. 2011;33(7):829-37.
• ⁶
  Astrand P, Rodahl K. Textbook of work physiology; physiological bases of exercise. 4th Ed. New York, McGraw-Hill, 1986.
• ⁷
  Morhardt JE, Morhardt SS. Correlations between heart rate and oxygen consumption in rodents. Am J Physiol. 1971; 221:1580-86.
• ⁸
  Trask AJ, Delbin MA, Katz PS, Zanesco A, Lucchesi PA. Differential coronary resistance microvessel remodeling between type 1 and type 2 diabetic mice: impact of exercise training. Vasc Pharmacol. 2012;57:187-93.
• ⁹
  de Moraes C, Davel AP, Rossoni LV, Antunes E, Zanesco A. Exercise training improves relaxation response and SOD-1 expression in aortic and mesenteric rings from high caloric diet-fed rats. BMC Physiol. 2008;8:12.
• ¹⁰
  Bender SB, Laughlin MH. Modulation of endothelial cell phenotype by physical activity: impact on obesity-related endothelial dysfunction. Am J Physiol Heart Circ Physiol. 2015;309(1):H1-8.
• ¹¹
  Donato AJ, Henson GD, Morgan RG, Enz RA, Walker AE, Lesniewski LA. TNF-α impairs endothelial function in adipose tissue resistance arteries of mice with diet-induced obesity. Am J Physiol Heart Circ Physiol. 2012;303:H672-9.
• ¹²
  Haynes WG. Interaction between leptin and sympathetic nervous system in hypertension. Curr Hypertens Rep. 2000;2(3):311-8.
• ¹³
  Korda M, Kubant R, Patton S, Malinski T. Leptin-induced endothelial dysfunction in obesity. Am J Physiol Heart Circ Physiol. 2008;295:H1514-21.
• ¹⁴
  Kleinbongard P, Heusch G, Schulz R. TNF alpha in atherosclerosis, myocardial ischemia/reperfusion and heart failure. Pharmacol Ther. 2010;127:295-314.
• ¹⁵
  Chen H, Montagnani M, Funahashi T, Shimomura I, Quon MJ. Adiponectin stimulates production of nitric oxide in vascular endothelial cells. J Biol Chem. 2003;278(45): 45021-6.
• ¹⁶
  Zhang H, Park Y, Zhang C. Coronary and aortic endothelial function affected by feedback between adiponectin and tumor necrosis factor α in type 2 diabetic mice. Arterioscler Thromb Vasc Biol. 2010;30(11):2156-63.
• ¹⁷
  Berg AH, Scherer PE. Adipose tissue, inflammation, and cardiovascular disease. Circ Res. 2005;96(9):939-49.
• ¹⁸
  Galili O, Versari D, Sattler KJ, Olson ML, Mannheim D, McConnell JP, et al. Early experimental obesity is associated with coronary endothelial dysfunction and oxidative stress. Am J Physiol Heart Circ Physiol. 2007;292(2):H904-11.
• ¹⁹
  Hajer GR, Van Haeften TW, Visseren FL. Adipose tissue dysfunction in obesity, diabetes, and vascular diseases. Eur Heart J. 2008;29:2959-71.
• ²⁰
  Centers for Disease Control and Prevention. Available from: https://www.cdc.gov/physicalactivity/
  » https://www.cdc.gov/physicalactivity/
• ²¹
  Booth FW, Roberts CK, Laye MJ. Lack of exercise is a major cause of chronic diseases. Compr Physiol. 2012;2(2):1143-211.
• ²²
  Haskell WL, Lee IM, Pate RR, Powell KE, Blair SN, Franklin BA, et al. Physical activity and public health: updated recommendation for adultsfrom the American College of Sports Medicine and the J Am Heart Assoc. 2007;116(9):1081-93.
• ²³
  da Nobrega AC. The subacute effects of exercise: concept, characteristics, and clinical implications. Exerc Sport Sci Rev. 2005;33:84-87.
• ²⁴
  Wilmore JH, Costill DL. Physiology of Sport and Exercise. Ed. (3rd) Champion, Illinois: Human Kinetics, 2004.
• ²⁵
  Garber CE, Blissmer B, Deschenes MR, Franklin BA, Lamonte MJ, Lee IM, et al. American College of Sports Medicine position stand. Quantity and quality of exercise for developing and maintaining cardiorespiratory, musculoskeletal, and neuromotor fitness in apparently healthy adults: guidance for prescribing exercise. Med Sci Sports Exerc. 2011;43:1334-59.
• ²⁶
  Hoydal MA, Wisloff U, Kemi OJ, Ellingsen O. Running speed and maximal oxygen uptake in rats and mice: practical implications for exercise training. Eur J Cardiovasc Prev Rehabil. 2007;14(6):753-60.
• ²⁷
  Delbin MA, Davel AP, Couto GK, de Araújo GG, Rossoni LV, Antunes E, et al. Interaction between advanced glycation end products formation and vascular responses in femoral and coronary arteries from exercise rats. PLoS One. 2012;7:e53318.
• ²⁸
  Goh J, Ladiges W. Voluntary wheel running in mice. Curr Protoc Mouse Biol. 2015;5(4):283-90.
• ²⁹
  Moraska A, Deak T, Spencer RL, Roth D, Fleshner M. Treadmill running produces both positive and negative physiological adaptations in Sprague-Dawley rats. Am J Physiol Regul Integr Comp Physiol. 2000;279:R1321-29.
• ³⁰
  de Bono JP, Adlam D, Paterson DJ, Channon KM. Novel quantitative phenotypes of exercise training in mouse models. Am J Physiol Integr Comp Physiol. 2006;290:R926-R934.
• ³¹
  Goh J, and Ladiges WC. A novel long term short interval physical activity regime improves body composition in mice. BMC Res Notes. 2013;6:66.
• ³²
  Taylor RS, Brown A, Ebrahim S, Jolliffe J, Noorani H, Rees K, et al. Exercise-based rehabilitation for patients with coronary heart disease: systematic review and meta-analysis of randomized controlled trials. Am J Med. 2004;116(10):682-92.
• ³³
  Thompson PD, Buchner D, Pina IL, Balady GJ, Williams MA, Marcus BH, et al. Exercise and physical activity in the prevention and treatment of atherosclerotic cardiovascular disease. Circulation. 2003;107(24):3109-3116.
• ³⁴
  Haram PM, Adams V, Kemi OJ, Brubakk AO, Hambrecht R, Ellingsen O, Wisløff U. Time-course of endothelial adaptation following acute and regular exercise. Eur J Cardiovasc Prev Rehabil. 2006;13(4):585-91.
• ³⁵
  Bacchi E, Negri C, Zanolin ME, Milanese C, Faccioli N, Trombetta M, et al. Metabolic effects of aerobic training and resistance training in type 2 diabetic subjects: a randomized controlled trial (the RAED2 study). Diabetes Care. 2012;35(4):676-682.
• ³⁶
  Busconi L, Michel T. Endothelial nitric oxide synthase; N-terminal myristoylation determines subcellular localization. J Biol Chem. 1993;268:8410-8413.
• ³⁷
  Kolluru GK, Siamwala JH, Chatterjee S. eNOS phosphorylation in health and disease. Biochimie. 2010;92:1186-1198.
• ³⁸
  Ortiz PA, Garvin JL. Trafficking and activation of eNOS in epithelial cells. Acta Physiol Scand. 2003;179:107-114.
• ³⁹
  Woodman CR, Muller JM, Laughlin MH, Price EM. Induction of nitric oxide synthase mRNA in coronary resistance arteries isolated from exercise-trained pigs. Am J Physiol. 1997;273:H2575-H2579.
• ⁴⁰
  Zanesco A, Antunes E. Effects of exercise training on the cardiovascular system: pharmacological approaches. Pharmacol Ther. 2007;114(3):307-317.
• ⁴¹
  Padilla J, Jenkins NT, Thorne PK, Martin JS, Rector RS, Davis JW, Laughlin MH. Transcriptome-wide RNA sequencing analysis of rat skeletal muscle feed arteries. II. Impact of exercisetraining in obesity. J Appl Physiol (1985). 2014;116(8):1033-47.
• ⁴²
  Xiang L, Naik J, Hester RL. Exercise-induced increase in skeletal muscle vasodilatory responses in obese Zucker rats. Am J Physiol Regul Integr Comp Physiol. 2005;288(4):R987-91.
• ⁴³
  Sebai M, Lu S, Xiang L, Hester RL. Improved functional vasodilation in obese Zucker rats following exercise training. Am J Physiol Heart Circ Physiol. 2011;301(3):H1090-6.
• ⁴⁴
  Touati S, Meziri F, Devaux S, Berthelot A, Touyz RM, Laurant P. Exercise reverses metabolic syndrome in high-fat diet-induced obese rats. Med Sci Sports Exerc. 2011;43(3):398-407.
• ⁴⁵
  Barbosa VA, Luciano TF, Vitto MF, Cesconetto PA, Marques SO, Souza DR, et al. Exercise training plays cardioprotection through the oxidative stress reduction in obese rats submitted to myocardial infarction. Int J Cardiol. 2012;157(3):422-4.
• ⁴⁶
  Barretti DL, Magalhães FC, Fernandes T, do Carmo EC, Rosa KT, Irigoyen MC, et al. Effects of aerobic exercise training on cardiac renin-angiotensin system in an obese Zucker rat strain. PLoS One. 2012;7(10):e46114.
• ⁴⁷
  Mostarda C, Moraes-Silva IC, Salemi VMC, Machi JF, Rodrigues B, De Angelis K, et al. Exercise training prevents diastolic dysfunction induced by metabolic syndrome in rats. Clinics (Sao Paulo). 2012;67(7):815-820.
• ⁴⁸
  Moraes-Silva IC, Mostarda C, Moreira ED, Silva KA, dos Santos F, de Angelis K, et al. Preventive role of exercise training in autonomic, hemodynamic, and metabolic parameters in rats under high risk of metabolic syndrome development. J Appl Physiol (1985). 2013;114(6):786-91.
• ⁴⁹
  Boa BC, Souza Md, Leite RD, da Silva SV, Barja-Fidalgo TC, Kraemer-Aguiar LG, Bouskela E. Chronic aerobic exercise associated to dietary modification improve endothelial function and eNOS expression in high fat fed hamsters. PLoS One. 2014;9(7):e102554.
• ⁵⁰
  Oharomari LK, Garcia NF, Freitas EC, Jordão Júnior AA, Ovídio PP, Maia AR, et al. Exercise training and taurine supplementation reduce oxidative stress and prevent endothelium dysfunction in rats fed a highly palatable diet. Life Sci. 2015;139:91-6.
• ⁵¹
  Pieri BL, Souza DR, Luciano TF, Marques SO, Pauli JR, Silva AS, et al. Effects of physical exercise on the P38MAPK/ REDD1/ 14-3-3 pathways in the myocardium of diet-induced obesity rats. Horm Metab Res. 2014;46(9):621-7.
• ⁵²
  Touati S, Montezano AC, Meziri F, Riva C, Touyz RM, Laurant P. Exercise training protects against atherosclerotic risk factors through vascular NADPH oxidase, extracellular signal- regulated kinase 1/2 and stress-activated protein kinase/c-Jun N-terminal kinase down regulation in obese rats. Clin Exp Pharmacol Physiol. 2015;42(2):179-85.

Publication Dates

• Publication in this collection
  2017

History

• Received
  14 Sept 2016
• Accepted
  03 Nov 2016