Content uploaded by Ana M Briones
Author content
All content in this area was uploaded by Ana M Briones on Jun 16, 2015
Content may be subject to copyright.
1 23
Current Hypertension Reports
ISSN 1522-6417
Curr Hypertens Rep
DOI 10.1007/s11906-013-0336-5
Exercise Training and Cardiometabolic
Diseases: Focus on the Vascular System
Fernanda R.Roque, Raquel Hernanz,
Mercedes Salaices & Ana M.Briones
1 23
Your article is protected by copyright and all
rights are held exclusively by Springer Science
+Business Media New York. This e-offprint is
for personal use only and shall not be self-
archived in electronic repositories. If you
wish to self-archive your work, please use the
accepted author’s version for posting to your
own website or your institution’s repository.
You may further deposit the accepted author’s
version on a funder’s repository at a funder’s
request, provided it is not made publicly
available until 12 months after publication.
HYPERTENSION AND OBESITY (E REISIN, SECTION EDITOR)
Exercise Training and Cardiometabolic Diseases:
Focus on the Vascular System
Fernanda R. Roque &Raquel Hernanz &
Mercedes Salaices &Ana M. Briones
#Springer Science+Business Media New York 2013
Abstract The regular practice of physical activity is a well-
recommended strategy for the prevention and treatment of
several cardiovascular and metabolic diseases. Physical ex-
ercise prevents the progression of vascular diseases and
reduces cardiovascular morbidity and mortality. Exercise
training also ameliorates vascular changes including endo-
thelial dysfunction and arterial remodeling and stiffness,
usually present in type 2 diabetes, obesity, hypertension
and metabolic syndrome. Common to these diseases is
excessive oxidative stress, which plays an important role
in the processes underlying vascular changes. At the vascu-
lar level, exercise training improves the redox state and
consequently NO availability. Moreover, growing evidence
indicates that other mediators such as prostanoids might be
involved in the beneficial effects of exercise. The purpose of
this review is to update recent findings describing the adap-
tation response induced by exercise in cardiovascular and
metabolic diseases, focusing more specifically on the
beneficial effects of exercise in the vasculature and the
underlying mechanisms.
Keywords Exercise training .Diabetes .Obesity .
Hypertension .Metabolic syndrome .Endothelial
dysfunction .Vascular remodeling .Stiffness .Oxidative
stress .Nitric oxide .Adipokines .Prostanoids
Introduction
According to the World Health Organization, of the estimated
57 million global deaths, approximately 63 % were due to
non-communicable diseases, and the largest proportion of
these deaths (48 %) is caused by cardiovascular disease [1].
Persuasive evidence indicates that 6-10 % of all deaths from
non-communicable diseases worldwide can be attributed to
physical inactivity [2]. Indeed, behavioral risk factors in-
cluding physical inactivity, tobacco use, unhealthy diet and
the harmful use of alcohol are associated with high blood
pressure, obesity, hyperglycemia and hyperlipidemia, and
they are estimated to be responsible for about 80 % of
coronary heart disease and cerebrovascular disease [1].
Regular practice of physical exercise prevents the progres-
sion of vascular diseases and reduces cardiovascular mor-
bidity and mortality, improving health substantially [2,3].
Particularly, physical activity attenuates cardiovascular dis-
ease mortality in individuals with metabolic risk factors
such as diabetes, obesity, hypertension and/or metabolic
syndrome [4]. Physical inactivity and a sedentary lifestyle
are believed to be independent risk factors for the develop-
ment of some metabolic and cardiovascular disorders. At
minimum, a weekly bout of moderate to vigorous physical
activity is protective in men and women with clustered
metabolic abnormalities [4]. Central to cardiometabolic
diseases are alterations in the structure and function of
conductance and resistance arteries. In metabolic syndrome,
both obesity and hypertension concomitantly occur with
F. R. Roque :M. Salaices :A. M. Briones
Departamento de Farmacología, Facultad de Medicina,
Universidad Autónoma de Madrid, Instituto de Investigación
Hospital Universitario La Paz (IdiPAZ), Madrid, Spain
R. Hernanz
Departamento de Bioquímica, Fisiología y Genética Molecular,
Universidad Rey Juan Carlos, Alcorcón, Spain
M. Salaices (*):A. M. Briones (*)
Department of Pharmacology, Universidad Autónoma de Madrid,
Arzobispo Morcillo 4,
28029 Madrid, Spain
e-mail: mercedes.salaices@uam.es
e-mail: ana.briones@uam.es
Curr Hypertens Rep
DOI 10.1007/s11906-013-0336-5
Author's personal copy
diabetes, and it might be difficult to discern whether vascu-
lar alterations derive from one or several specific diseases or
from the combined mechanisms of all [5]. This review
summarizes recent findings on the effects of exercise in
the function, structure and mechanics of arteries in
cardiometabolic pathologies and focuses on new aspects of
the underlying mechanisms responsible for these effects.
Exercise and Type 2 Diabetes Mellitus
Type 2 diabetes mellitus (T2DM) is a complex metabolic
disease characterized by insulin resistance, hyperglycemia,
early decrements in the insulin secretory capacity and vas-
cular dysfunction even in a prediabetic stage [6,7]. T2DM
is an independent risk factor for vascular disease and is often
associated with other cardiovascular disease risk factors,
including high blood pressure, dyslipidemia, obesity and
physical inactivity [8].
T2DM is associated with impaired endothelial-dependent
vasodilatation, increased contractile response of vascular
smooth muscle and a predisposition to the development of
inflammatory, thrombotic and atherosclerotic events [7,
9–13]. Numerous studies have demonstrated that the expo-
sure of vascular endothelium to high circulating levels of
lipids and glucose is accompanied by reduced NO availabil-
ity [14,15]. In addition, hyperglycemia and impaired
suppression of adipose tissue lipolysis may lead to intracel-
lular changes in the redox state increasing the formation of
reactive oxygen species (ROS), which is an important factor
in the development of endothelial dysfunction. The in-
creased nonenzymatic glycation and production of advanced
glycation end products and increased activity of the polyol
pathway induced by hyperglycemia increase ROS produc-
tion via NADPH oxidase, the most important source of
superoxide anion in the vasculature [15,16]. Therefore,
the overproduction of ROS, through their NO-scavenging
effect, is involved in T2DM-induced vascular dysfunction.
Dysregulation of adipokine expression and dyslipidemia
also participate in altered vascular function. Therefore,
endothelial dysfunction may be a critical early target for
preventing atherosclerosis and cardiovascular disease in
patients with diabetes or insulin resistance.
Reduced cardiovascular morbidity and mortality have
been associated with increased regular physical activity
and physical fitness in T2DM patients [17,18]. In fact,
exercise training has long been recognized as an important
basis for the prevention and management of diabetes due to
significant improvements in glycemic control, insulin sen-
sibility, vascular function and reduction of blood pressure
and triglyceride levels [19•,20•]. Different types of super-
vised exercise training improve glycemic control and reduce
HbA
1c
as reviewed recently [21]. Specifically, aerobic and
combined aerobic/resistance, but not resistance exercise
training, reduces HbA
1c
levels. Importantly, the frequency
of exercise sessions in T2DM patients may be the major
determinant of glycemic control rather than the duration or
intensity of the sessions [21]. Another interesting question
is based on how long the beneficial effects of exercise
persist after cessation. Li et al. [22] observed that the
persistent training-induced improvements in insulin sensi-
tivity may be more dependent on exercise duration than
exercise intensity.
Although the beneficial effects of exercise training on the
improvement of energy metabolism and insulin sensitivity
are well established, only recently the effects and mecha-
nisms whereby exercise training ameliorates vascular func-
tion in T2DM have been elucidated. The potential of
exercise training in reverse endothelial dysfunction is well
documented in several studies performed in diabetic rodents
[12,20•,23–25] and prediabetic and diabetic patients
[26–29]. Of note, this is true for both conduit (aorta and
brachial arteries) and resistance vessels (coronaries and
forearm arteries), suggesting that exercise exerts beneficial
effects in the whole vascular system and not only in the
more actively exercised vascular beds. With respect to the
type of exercise, combined exercise training (aerobic plus
resistance) is effective improving endothelial function in
different arterial beds from animal models and diabetic
patients [26,28,29]. It is now evident that increases in
NO bioavailability, mainly by the reduction of oxidative
stress and inflammation, are important contributors to the
improvement of endothelial function observed with low to
moderate intensity aerobic exercise training in T2DM mice
[30••]. Moreover, improved endothelial NO synthase
(eNOS) phosphorylation and increased antioxidant enzyme
expression have been observed in diabetic mice after aerobic
exercise training [12,20•,23,25]. Additionally, exercise
affects the levels and/or expression of proinflammatory cy-
tokines that have a role in the decreased NO bioavailability
due to increased ROS generation [31] and stimulates che-
mokine production [32]. Thus, aerobic exercise training
reduced TNF-αandIL-6levelsincoronaryarterioles
[20•], but not in aorta [24] from T2DM mice. This
discrepancy may result from differences in the arterial
bed evaluated or the duration of physical training pro-
tocols. In fact, in T2DM mice, 6 but not 2 weeks of
aerobic exercise training reduces plasma high-sensitive
C-reactive protein (CRP) levels [24], suggesting that
more prolonged exercise periods might be required to
reduce inflammatory markers.
Adipose tissue serves as a highly active metabolic and
endocrine organ regulating lipid and glucose metabolism. In
addition, adipose tissue produces a large number of cyto-
kines, chemokines and hormones, and some evidence sug-
gests that the vascular dysfunction observed in insulin
Curr Hypertens Rep
Author's personal copy
resistance, diabetes and obesity states may be influenced by
altered signaling from adipose tissue to blood vessels
[33–35]. In fact, the uncontrolled secretion of adipocyte-
and adipose tissue-derived factors occurring in diabetic
and/or obesity states promotes a systemic inflammatory
state [34]. Interestingly, plasma levels of adiponectin, an
antiinflammatory and protective adipokine, are markedly
reduced in patients and rodent models of diabetes [25,36],
and this is closely related to endothelial dysfunction [37,
38]. More importantly, aerobic exercise training increased
serum and aorta adiponectin expression in T2DM mice, and
this might have a role in reducing inflammation by decreas-
ing IFN-γand oxidative stress [25]. In another study, Sixt et
al. [29] observed that after 6 months of exercise, despite
continued improvement in endothelial dysfunction, the
levels of fasting plasma glucose, CPR, HbA1c and
adiponectin returned to levels comparable to those measured
at the beginning of the study, and there was also a slight
regain in weight when the 5 months of intervention were
performed at home [29]. This indicates the need for prefer-
ably supervised out-patient rehabilitation programs.
Kadoglou et al. [39] studied the impact of long-term aerobic
exercise training on the serum levels of the adipokines
apelin and ghrelin in T2DM patients. Apelin seems to play
a key role in the regulation of vascular tone and cardiovas-
cular function [40], and ghrelin plays a protective role and
possesses antiinflammatory properties in atherosclerosis
[41,42]. Twelve weeks of structured exercise training
upregulated serum apelin levels and improved the metabolic
profile but had negligible effects on body weight and on
serum levels of ghrelin in the whole study population [39].
Interestingly, an increased ghrelin concentration was ob-
served in exercise-treated women, despite the absence of
weight loss [39]. How these mediators participate in the
improvement of the endothelial dysfunction observed after
exercise is unknown.
In addition to endothelial dysfunction, the arterial struc-
ture and biomechanics can be used to detect early alterations
related to vascular dysfunction in T2DM. In large arteries
from T2DM patients, the main structural modification ob-
served is increased intima-media thickness associated with
increased arterial stiffness [43,44], whereas in small arteries
hypertrophic remodeling has been observed [45–47]. In
animals, depending on the vascular bed, hypertrophic in-
ward or outward remodeling can be observed in T2DM [48,
49,50•]. Interestingly, opposed to that observed in diabetic
macrovessels where diabetes leads to increased vascular
wall stiffness, the diabetic coronary arterioles were less stiff
possibly because of the increased elastin mRNA content
[48]. The effects of exercise training on vascular remodeling
and mechanical properties of T2DM individuals have only
been investigated by a few studies. More importantly, most
of the studies are still descriptive, and there is a paucity of
information regarding the mechanisms responsible for the
beneficial effects of exercise in these aspects. Six months
of intensive lifestyle intervention in patients (including
achieved and maintained modest weight loss, accomplish-
ment of a recommended dietary intake and completion of
physical activity of moderate intensity) reduces carotid ar-
tery intima-media thickness [51]. In db/db mice, 8 weeks of
aerobic exercise training partially reverse the adverse coro-
nary resistance remodeling evidenced by a decreased wall:
lumen ratio and growth index [50•]. However, the effects of
exercise training on vascular mechanics are discouraging.
The supervised exercise training, including both endurance
and muscle strength for 24 months in patients with T2DM,
did not improve conduit arterial elasticity despite improved
metabolic control and significant cardiovascular risk reduc-
tion [52]. Moreover, in coronary resistance microvessels
from db/db mice, exercise did not affect vessel stiffness
[50•]. The reasons for this lack of beneficial effects of
exercise are unknown.
Exercise and Obesity
Obesity is a chronic disease characterized by excessive fat
accumulation and increased morbidity and mortality. The
visceral obesity has a major role in the development of
metabolic and cardiovascular disorders such as elevated
blood pressure, dyslipidemia, impaired glucose tolerance
and insulin resistance [13,53]. Besides obesity-related dis-
orders, the visceral adiposity individually impairs endothe-
lial function and increases the intima-media and vascular
media thickness and arterial stiffness [31,54,55].
Interestingly, a recent study demonstrated that excess adi-
posity, regardless of anatomical distribution pattern, is asso-
ciated with impaired endothelial function [56]. Obese
hypertrophic adipocytes secrete several adipokines capable
of directly affecting endothelial function and promote a
systemic inflammatory state. In fact, the anticontractile
function of perivascular adipose tissue is attenuated or
completely lost in obesity [54]. Systemic and local
inflammation associated with oxidative stress, adipokine
dysregulation and increased sympathetic nervous actions is
implicated in endothelial dysfunction in obesity [54].
Proinflammatory cytokines such as TNF-αor IL-6 possibly
released from macrophages [57], aldosterone or other
mineralocorticoid receptor agonists released from adipo-
cytes [35] and angiotensin II or leptin [34], among other
factors, are all increased in obesity and are examples of
substances that can decrease NO production and/or bioavail-
ability. This represents the key mechanism underlying en-
dothelial dysfunction in obesity [13,54].
Lifestyle changes are an indispensable approach in the
treatment of obesity, and exercise is one of the most
Curr Hypertens Rep
Author's personal copy
important strategies to treat this pathology [53,58]. Regular
physical activity has a powerful protective effect against
obesity-related comorbidities, contributing not only to in-
creased energy expenditure, enhancing long-term weight
loss and preventing weight regain, but also protecting
against loss of lean body mass, improving the cardiovascu-
lar performance and lipid profile, reducing blood pressure
and the risk of T2DM, among others [58,59]. No consensus
exists on the amount of exercise needed, but it is clear that
these prescriptions should emphasize the use of major mus-
cle groups and engage the cardiovascular and musculoskel-
etal system, always taking into account the main needs of
each specific group, such as children, adults and the elderly
[58,59].
Growing evidence indicates that exercise training im-
proves or attenuates the progression of endothelial dysfunc-
tion in experimental models of obesity [60–63]. Indeed, in
diet-induced obese rats exercise training improved the re-
laxation response in both aortic and superior mesenteric
arteries directly mediated by an increased NO bioavailabil-
ity due to Cu/Zn-SOD upregulation [61]. The effect of
exercise improving aortic vasodilation induced by acetyl-
choline [62] and vasodilation of skeletal muscle arterioles
induced by insulin [63] in obesity also appears to be medi-
ated by NO. In humans, exercise training also decreases the
cardiovascular risk profile and improves endothelial func-
tion [64–67]. Indeed, in obese adults a program of 12 weeks
of aerobic exercise training at either high or moderate
intensities or high-intensity strength training improves en-
dothelial function on the brachial artery [66]. However,
interestingly the high-intensity aerobic interval training
resulted in a greater improvement in endothelial function,
possibly because of greater shear stress-induced high-
intensity aerobic training during exercise [66]. Moreover,
in overweight and obese men habitual aerobic exercise
training intervention for 12 weeks (3 days/week of walking
and jogging) reduced body weight, decreased the plasma
endothelin-1 concentration and increased nitrite production
besides increasing central arterial distensibility, thus
contributing to an improvement in endothelial function
[68]. However, in this study it is not clear whether the
weight loss or the aerobic exercise was responsible for the
benefits of exercise on arterial function. In the same line of
evidence, another study showed that the regular moderate
intensity aerobic exercise (5-7 days/ week during 12 weeks)
improved endothelium-dependent vasodilation in over-
weight and obese adults even in the absence of changes in
body mass and composition [69], suggesting that the bene-
fits of exercise in the vascular system involve more than the
amount of fat and should be considered as a general measure
of cardiovascular protection in obesity. More recently, Vinet
et al. [70] demonstrated that compared with normal-weight
men, obese men had higher carotid intima-media thickness,
lower carotid distensibility, and conduit and resistance ves-
sel endothelial dysfunction. Importantly, short-term low-
intensity exercise training (8 weeks) improved the distensi-
bility and endothelium-dependent vasodilatation in the large
conduit artery, but not in the resistance artery, demonstrating
heterogeneity in training-induced vascular responses.
Distinct regulation patterns between conduit and smaller
peripheral vessels could explain the different effects of
exercise training. In addition, a more intense or prolonged
training may be required to achieve adaptive changes in
resistance vessels. Indeed, to date few studies have shown
the effects of exercise training on impaired microcirculation
in obesity. Alterations of retinal vessel diameters and
arteriolar-to-venular diameter ratio (AVR) have been shown
to predict cardiovascular morbidity and mortality, and phys-
ical fitness seems to play a central role in the regulation of
the retinal microcirculation. The continuous aerobic exercise
and anaerobic interval-training program (10 weeks) in obese
individuals improved the impaired AVR, probably through
improvement of endothelial function in retinal arterioles
[71]. This suggests that regular exercise has the potential
to improve microvasculature, although further studies in-
cluding physically inactive individuals are needed to better
understand the effects of exercise training in the retinal
microvasculature and in the different small vascular beds
in obesity.
Exercise and Hypertension
A large body of evidence indicates that vascular func-
tional, structural and mechanical alterations, such as im-
pairment of endothelium-dependent vasodilator responses
and enhancement of the vasoconstrictor response to dif-
ferent agonists, increased wall:lumen ratio and vascular
stiffness are associated with hypertension [72–74,75••,
76]. Central to these alterations is impaired NO avail-
ability secondary to oxidative stress production and in-
creased cyclooxygenase-derived contractile products
[72,73,75••,77,78••]. Besides pharmacological treat-
ments, it is evident that several non-pharmacological
approaches, including physical exercise and dietary in-
terventions, can improve blood pressure control and
vascular alterations in hypertension.
Regular exercise has been recommended as a strategy for
the prevention and treatment of hypertension [79–82] even
in individuals with a parental history of hypertension [83]. It
is well established that aerobic exercise training decreases
blood pressure [84] through a reduction of vascular resis-
tance [85,86]. In addition, aerobic exercise training im-
proves vascular function in vessels from hypertensive
patients and animal models [87,88]. However, there are
few studies about the effects of resistance exercise training
Curr Hypertens Rep
Author's personal copy
or the combination of resistance plus aerobic exercise on
blood pressure, and although some data suggest that this
modality of exercise reduces blood pressure, more studies
need to be performed [84,89]. Not only is the type
(aerobic vs. resistance) of exercise important, but also
the modality (i.e., running vs. swimming) an important
factor. Thus, recent findings demonstrate that swimming
aerobic exercise (12 weeks) is also effective in eliciting
hypotensive effects, improving vascular function and in-
creasing compliance of the carotid artery from older
adults [90•]. This is an important issue since this type
of exercise is ideal for older adults. In addition, the
quantity and/or the intensity of exercise also determine
effects on blood pressure. Indeed, although most of the
studies in hypertension investigate the effects of regular
moderate aerobic exercise training, recent lines of study
have emphasized the need to determine whether contin-
uous vs. interval training or moderate vs. intense exercise
might lead to more pronounced cardiovascular changes in
hypertension [91]. Another point that deserves attention
is the fact that most of the studies exploring the benefi-
cial effects of exercise on vascular alterations associated to
hypertension are performed in large arteries, but small arteries
are mainly involved in the regulation of blood pressure. In
resistance arteries of the gastrocnemius muscle, swimming
training improved the responses to acetylcholine- and flow-
mediated dilatation in rats with chronic NOS inhibition [92].
In addition, we have recently demonstrated that small arteries
from spontaneously hypertensive rats (SHR) also show im-
proved relaxation after exercise [88].
Factors involved in the pathophysiology of hypertension,
such as activation of the sympathetic nervous system,
upregulation of the renin-angiotensin system, altered G
protein-coupled receptor signaling and inflammation, are
strongly related to oxidative stress [78••]. Improved
endothelium-dependent responses induced by regular exer-
cise training have been demonstrated in hypertensive
humans [93] and animal models [94] mainly through a
significant increase in NO production and/or decrease in
NO inactivation by oxidative stress [88,93,95]. In fact,
increasingly emerging evidence demonstrates that diverse
beneficial effects induced by exercise training in vascular
changes observed in hypertension are mainly mediated by
reduction of oxidative stress. Aerobic exercise training de-
creases oxidative stress by increasing the efficiency of the
antioxidant system [30••,88,96••]. In fact, in both large
arteries, such as aorta, and in coronary and mesenteric
arteries, aerobic exercise training attenuated the oxidative
stress observed in hypertensive rats and increased Mn or
CuZn-SOD protein expression [88,97]. Importantly, recent
studies demonstrated that in SHR even a single bout of
exercise, either aerobic (moderate or high intensity) or
resistance exercise, increases endothelium-dependent
relaxation through NO pathways [98–100]. Indeed,
moderate- or high-intensity exercise was able to improve
the reduced insulin- and insulin growth factor (IGF)-1-
induced vessel relaxation response [98,99], and it was
related to increased phosphatidylinositol 3-kinase (PI3K)
and NOS activation, which in turn was associated with
the reduced level of superoxide production in high-
intensity exercise, therefore contributing to the exercise-
induced amelioration in the vascular dysfunction of
hypertensive rats [99].
The beneficial effects of exercise training in improving
vasodilator capacity are related not only with improved NO
availability but also other vasodilators. In the aorta of SHR,
Silva et al. [101] demonstrated that swimming training
(8 weeks) improved the vasodilator effect of angiotensin
(1-7) through an endothelium-dependent mechanism involv-
ing NO and prostacyclin. In addition, the swimming training
increased the protein expression of the Mas receptor. At
the skeletal muscle level, the aerobic training (8 weeks)
normalized the reduced capacity of hypertensive subjects
to form adenosine and prostacyclin [102]. Interestingly, the
combined aerobic plus resistance training at moderate inten-
sity (16 weeks) decreased vasoconstrictor compounds such
as thromboxane A
2
(TXA
2
) and ATP and increased vasodi-
lator compounds such as prostacyclin in the muscle vastus
lateralis of individuals with essential hypertension [103],
demonstrating that prostanoids and nucleotides may also
be important players in the observed training-induced
lowering of blood pressure in hypertensive individuals.
This is supported by our recent findings in mesenteric
resistance arteries from SHR where exercise training re-
versed the augmented contractile response induced by the
TXA
2
analog U46619 and reduced the cyclooxygenase-
TP-dependent component of acetylcholine-induced con-
tractile responses [88].
Besides the improvement in endothelial function, the
increased arterial stiffness, considered an indicator of sub-
clinical organ damage in hypertension [104], was reduced in
large arteries from hypertensive patients submitted to inter-
val exercise training [105] and in young men with family
histories of hypertension after short-term moderate-intensity
aerobic exercise training programs [106]. Recently, we
demonstrated that exercise training improved vascular
stiffness in both coronary and small mesenteric arteries
of SHR [88] although exercise did not modify the
increased wall:lumen ratio. These effects on vessel stiff-
ness were associated with improvements in the altered
internal elastic lamina structure and collagen deposition
by effects in matrix metalloproteinases expression [88].
Other authors have also demonstrated that exercise im-
proves altered extracellular matrix deposition in hyper-
tension [107,108]. However, depending on the vascular
bed studied, either improvement [109–111]ornoeffects
Curr Hypertens Rep
Author's personal copy
[88,110] of exercise training on vascular structure have
been observed, suggesting that exercise periods that are
prolonged, more intense or started earlier might be needed to
improve altered vascular structure in hypertension.
Apart from effects on vascular remodeling and mechanics,
our recent findings demonstrate that aerobic exercise train-
ing also induces modifications at the level of the microcir-
culation correcting capillary rarefaction and promoting a
balance between angiogenic and apoptotic factors to
prevent microvascular abnormalities in hypertension
[112•]. In addition, the decrease in oxidative stress induced
by aerobic exercise training in SHR seems to be associated
with the normalization of the reduced number of endothelial
progenitor cells observed in hypertension in a vascular
endothelial growth factor (VEGF)/eNOS-dependent pathway,
thus promoting a peripheral revascularization in trained
hypertensive rats [113].
Exercise and Metabolic Syndrome
Metabolic syndrome is a complex of interrelated risk factors
for cardiovascular disease characterized by the presence of
central obesity, raised blood pressure, dyslipidemia and
dysglycemia [114]. Endothelial dysfunction should be more
prevalent in patients with metabolic syndrome since all
components of this syndrome have adverse effects on the
endothelium [115]. Indeed, several studies showed that
endothelium-dependent vasodilation is impaired in patients
with metabolic syndrome [115], and in fact, an increased
number of metabolic syndrome components is associated
with more severe impairment in endothelial function
[115]. As expected, inflammation and oxidative stress
play key roles in the pathophysiology of this syndrome
[115,116,117••].
According to current guidelines, lifestyle measures are
the first-line treatment of metabolic syndrome [118].
Importantly, physical activity attenuates cardiovascular
disease mortality in individuals with metabolic risk factors
[4]. As described above, the beneficial effects of regular
physical activity in reducing inflammation and blood
pressure, restoring insulin function and glucose tolerance,
and improving muscular metabolism are among the reasons
for using exercise as a lifestyle measure to prevent the onset
of new risk factors and/or treat the already existing risk
factors in metabolic syndrome [116,117••]. Regarding the
type and duration of exercise needed to induce these
beneficial effects, although the effect of longer training
interventions, especially combination training regimes,
needs to be studied more in the future, evidences indicate
that aerobic exercise may be more beneficial to modify risk
factors of patients with metabolic syndrome than strength
training [119]. In addition, it has been debated whether high-
intensity training [120,121,122•]orlow-tomoderate-
intensity training [123] is more advantageous.
Exercise training has been reported to improve the
endothelial function observed in patients with metabolic
syndrome [120,121,122•,124] and in obese Zucker rats
[125–127]. In the above-mentioned studies, the endothelial
function of patients with metabolic syndrome was mainly
evaluated in conduit arteries, but studies performed in ani-
mals demonstrated that exercise training also improves the
endothelial function of resistance vessels (skeletal muscle
arterioles) [126,127], even in nonexercise trained muscle
[127], demonstrating an important global effect of exercise
training on vascular function. In fact, exercise training im-
proves the NO and prostacyclin pathways in obese Zucker
rats [125]. Insulin resistance and metabolic disorders are
associated with an impaired arachidonic acid metabolism
and accumulation of prostaglandin H
2
and/or TXA
2
, con-
tributing to elevated TP activation and impaired functional
vasodilation via increased vascular ROS in obese Zucker
rats [128]. More recently, Sebai et al. [127] showed that the
improved vasodilation induced by exercise training on
both activated and not activated skeletal muscle arterioles
was related to decreased TP-mediated vasoconstriction
associated with improved insulin resistance. These results
demonstrate that at least in small vessels, other mecha-
nisms in addition to NO might collaborate to improve
vascular function induced by exercise training in metabolic
syndrome.
In addition to vascular function, the severity of arte-
rial stiffness is attenuated by high cardiorespiratory
fitness in men with metabolic syndrome [129], and even
short-term aerobic exercise reduces arterial stiffness in
older adults with T2DM complicated by comorbid
hypertension and hyperlipidemia [130]. These results
suggest that even in patients at very high risk of cardiovas-
cular damage, exercise provides beneficial effects at the
vascular level.
Conclusions
Metabolic disorders such as metabolic syndrome are asso-
ciated with vascular dysfunction and altered wall structure
and mechanics. The mechanisms responsible for these effects
include indirect mechanisms such as insulin-resistance, dia-
betes mellitus, hypertension and dyslipidemia. In fact, this
myriad of factors creates a vicious circle of inflammation-
mediated vascular damage. Growing evidence demonstrates
that the production of adipokines and/or proinflammatory
molecules released by adipose tissue and other organs has a
deleterious effect on the vascular wall. Pivotal to vascular
alterations in these pathologies is oxidative stress that in turn
leads to reduced NO availability (Fig. 1).
Curr Hypertens Rep
Author's personal copy
It is now evident that regular practice of low- to
moderate-intensity exercise induces beneficial effects in
cardiovascular and metabolic diseases. In fact, aerobic
exercise is recommended for the management of T2DM,
obesity, hypertension and metabolic syndrome. However,
questions arise about the frequency and/or duration of
the exercise sessions and whether high-intensity aerobic
training, resistance training or the combination of aero-
bic plus resistance training would be more beneficial.
Besides improving the altered metabolic profile, exercise
training also improves most of the vascular alterations
associated with cardiovascular and metabolic diseases.
More specifically, exercise training improves the endo-
thelial dysfunction, altered vascular structure and in-
creased vascular stiffness usually observed in clinical
and/or experimental models of T2DM, obesity, hyper-
tension and metabolic syndrome. Importantly, these
beneficial effects are observed not only in arteries from
exercised-tissues, but also in other vascular territories,
thus providing a putative explanation of the beneficial
effects of exercise in parameters such as blood pressure.
To date, increased NO bioavailability due to the reduced
oxidative stress and improved antioxidant defense sys-
tem seems to be the main mechanism responsible for
the improvement of endothelium-dependent responses
and for structural and stiffness alterations induced by
exercise (Fig. 1). However, growing evidences suggest
that the beneficial effects of exercise training might
affect additional pathways such as cyclooxygenase-
derived products and/or components of the renin-
angiotensin system, among others. All together, these
findings demonstrate that the beneficial effects of exer-
cise training on vascular function and remodeling in
cardiometabolic diseases might contribute to the im-
provement of cardiovascular risk associated with these
pathologies. The door is open to the possibility of
designing specific training protocols depending on the
disease or the patients.
Fig. 1 Obesity, hypertension, diabetes, dyslipidemia and metabolic
syndrome are key elements of cardiovascular disease in which a central
element is vascular damage, particularly endothelial dysfunction and
altered wall structure and stiffness. Pivotal mechanisms responsible for
these alterations are inflammation and oxidative stress, although addi-
tional metabolic or hemodynamic parameters are also responsible for
vascular changes. Different types of exercise training diminish the
endothelial dysfunction, altered vascular structure and/or increased
vascular stiffness observed in these pathologies. Mechanisms
responsible for the beneficial effects of exercise at the vascular level
include improved nitric oxide (NO) availability, increased antioxidant
defenses, and increased or reduced vasodilator or vasoconstrictor
prostanoids, respectively. Additionally, improved glucose and lipopro-
tein metabolism, decreased hemodynamic stress and improved protec-
tive adipokine production together with reduction of inflammatory
adipokines might also contribute to the beneficial effects of exercise
on the vascular system
Curr Hypertens Rep
Author's personal copy
Acknowledgments Studies performed by the authors were supported
by grants from the Ministerio de Economía y Competitividad
(SAF2009-07201, SAF2012-36400), Instituto de Salud Carlos III (Red
RECAVA, RD06/0014/0011, Retic Enfermedades Cardiovasculares
RD12/0042/0024), Fundación Mutua Madrileña and Fundación Mapfre.
AMB is supported by the Ramón y Cajal Program (RYC-2010–06473).
FR Roque was the recipient of a CAPES-Brazil scholarship.
Conflict of Interest F.R. Roque declares no conflict of interest.
R. Hernanz declares no conflict of interest.
M. Salaices declares no conflict of interest.
A.M. Briones declares no conflict of interest.
References
Papers of particular interest, published recently, have been
highlighted as:
•Of importance
•• Of major importance
1. http://www.who.int/gho/ncd/mortality_morbidity/en/index.html.
Accessed January 2013.
2. Lee IM, Shiroma EJ, Lobelo F, et al. Effect of physical
inactivity on major non-communicable diseases worldwide:
an analysis of burden of disease and life expectancy. Lancet.
2012;380:219–29.
3. Lee DC, Artero EG, Sui X, et al. Mortality trends in the general
population: the importance of cardiorespiratory fitness. J
Psychopharmacol. 2010;24:27–35.
4. Hamer M, Stamatakis E. Low-dose physical activity attenuates
cardiovascular disease mortality in men and women with
clustered metabolic risk factors. Circ Cardiovasc Qual Outcomes.
2012;5:494–9.
5. Virdis A, Neves MF, Duranti E, et al. Microvascular endothelial
dysfunction in obesity and hypertension. Curr Pharm Des. 2012
Nov 19. (Epub ahead of print).
6. Inzucchi SE. Diagnosis of diabetes. N Engl J Med. 2012;367:542–
50.
7. Park Y, Wu J, Zhang H, et al. Vascular dysfunction in type 2
diabetes: emerging targets for therapy. Expert Rev Cardiovasc.
2009;7:209–13.
8. Gerich JE. Type 2 diabetes mellitus is associated with multiple
cardiometabolic risk factors. Clin Cornerstone. 2007;8:53–68.
9. Johnstone MT, Creager SJ, Scales KM, et al. Impaired
endothelium-dependent vasodilation in patients with insulin-
dependent diabetes mellitus. Circulation. 1993;88:2510–6.
10. Schmidt AM, Crandall J, Hori O, et al. Elevated plasma levels of
vascular cell adhesion molecule-1 (VCAM-1) in diabetic patients
with microalbuminuria: a marker of vascular dysfunction and
progressive vascular disease. Br J Haematol. 1996;92:747–50.
11. Schalkwijk CG, Stehouwer CD. Vascular complications in diabe-
tes mellitus: the role of endothelial dysfunction. Clin Sci (Lond).
2005;109:143–59.
12. Moien-Afshari F, Ghosh S, Elmi S, et al. Exercise restores endo-
thelial function independently of weight loss or hyperglycaemic
status in db/db mice. Diabetologia. 2008;51:1327–37.
13. Davel AP, Wenceslau CF, Akamine EH, et al. Endothelial dys-
function in cardiovascular and endocrine-metabolic diseases: an
update. Braz J Med Biol Res. 2011;44:920–32.
14. Cersosimo E, DeFronzo RA. Insulin resistance and endothelial
dysfunction: the road map to cardiovascular diseases. Diabetes
Metab Res Rev. 2006;22:423–36.
15. Hadi HA, Suwaidi JA. Endothelial dysfunction in diabetes
mellitus. Vasc Health Risk Manag. 2007;3:853–76.
16. Wautier MP, Chappey O, Corda S, et al. Activation of NADPH
oxidase by AGE links oxidant stress to altered gene expression
via RAGE. Am J Physiol Endocrinol Metab. 2001;280:E685–94.
17. Telford RD. Low physical activity and obesity: causes of
chronic disease or simply predictors? Med Sci Sports
Exerc. 2007;39:1233–40.
18. Cardoso CR, Maia MD, de Oliveira FP, et al. High fitness is
associated with a better cardiovascular risk profile in patients with
type 2 diabetes mellitus. Hypertens Res. 2011;34:856–61.
19. •Chudyk A, Petrella RJ. Effects of exercise on cardiovascular
risk factors in type 2 diabetes. Diabetes Care. 2011;34:1228–37.
This is a systematic review representative of the effect of aerobic
or resistance exercise training on clinical markers of cardiovas-
cular risk in patients with T2DM.
20. •Lee S, Park Y, Zhang C. Exercise training prevents coronary
endothelial dysfunction in type 2 diabetic mice. Am J Biomed Sci.
2011;3:241–52. This study demonstrates that increased NO bio-
availability and decreased inflammation are related to the effects of
exercise training in restoring endothelial function in T2DM.
21. Umpierre D, Ribeiro PA, Schaan BD, et al. Volume of supervised
exercise training impacts glycaemic control in patients with type
2 diabetes: a systematic review with meta-regression analysis.
Diabetologia. 2013;56:242–51.
22. Li J, Zhang W, Guo Q, et al. Duration of exercise as a key
determinant of improvement in insulin sensitivity in type 2 dia-
betes patients. Tohoku J Exp Med. 2012;227:289–96.
23. Moien-Afshari F, Ghosh S, Elmi S, et al. Exercise restores coro-
nary vascular function independent of myogenic tone or hyper-
glycemic status in db/db mice. Am J Physiol Heart Circ Physiol.
2008;295:H1470–80.
24. Sallam N, Khazaei M, Laher I. Effect of moderate-intensity
exercise on plasma C-reactive protein and aortic endothelial
function in type 2 diabetic mice. Mediat Inflamm.
2010;2010:149678.
25. Lee S, Park Y, Dellsperger KC, et al. Exercise training improves
endothelial function via adiponectin-dependent and independent
pathways in type 2 diabetic mice. Am J Physiol Heart Circ
Physiol. 2011;301:H306–14.
26. Maiorana A, O'Driscoll G, Cheetham C, et al. The effect of
combined aerobic and resistance exercise training on vascular
function in type 2 diabetes. J Am Coll Cardiol. 2001;38:860–6.
27. Desch S, Sonnabend M, Niebauer J, et al. Effects of physical
exercise versus rosiglitazone on endothelial function in coronary
artery disease patients with prediabetes. Diabetes Obes Metab.
2010;12:825–8.
28. Okada S, Hiuge A, Makino H, et al. Effect of exercise interven-
tion on endothelial function and incidence of cardiovascular
disease in patients with type 2 diabetes. J Atheroscler Thromb.
2010;17:828–33.
29. Sixt S, Beer S, Blüher M, et al. Long- but not short-term multi-
factorial intervention with focus on exercise training improves
coronary endothelial dysfunction in diabetes mellitus type 2 and
coronary artery disease. Eur Heart J. 2010;31:112–9.
30. •• de Lemos ET, Oliveira J, Pinheiro JP, et al. Regular physical
exercise as a strategy to improve antioxidant and anti-inflammatory
status: benefits in type 2 diabetes mellitus. Oxidative Med Cell
Longev. 2012. doi:10.1155/2012/741545.This review demonstrates
the impact of regular physical exercise as an antioxidant and anti-
inflammatory strategy to prevent evolution of type 2 diabetes.
31. Sturm W, Sandhofer A, Engl J, et al. Influence of visceral obesity
and liver fat on vascular structure and function in obese subjects.
Obesity (Silver Spring). 2009;17:1783–8.
32. Van Dyke TE, Kornman KS. Inflammation and factors that may
regulate inflammatory response. J Periodontol. 2008;79:1503–7.
Curr Hypertens Rep
Author's personal copy
33. Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J
Clin Endocrinol Metab. 2004;89:2548–56.
34. Hajer GR, van Haeften TW, Visseren FL. Adipose tissue dys-
function in obesity, diabetes, and vascular diseases. Eur Heart J.
2008;29:2959–71.
35. Briones AM, Nguyen Dinh Cat A, Callera GE, et al. Adipocytes
produce aldosterone through calcineurin-dependent signaling
pathways: implications in diabetes mellitus-associated obesity
and vascular dysfunction. Hypertension. 2012;59:1069–78.
36. Hotta K, Funahashi T, Arita Y, et al. Plasma concentrations of a
novel, adipose-specific protein, adiponectin, in type 2 diabetic
patients. Arterioscler Thromb Vasc Biol. 2000;20:1595–9.
37. Shimabukuro M, Higa N, Asahi T, et al. Hypoadiponectinemia is
closely linked to endothelial dysfunction in man. J Clin
Endocrinol Metab. 2003;88:3236–40.
38. Tan KC, Xu A, Chow WS, et al. Hypoadiponectinemia is
associated with impaired endothelium-dependent vasodilation. J
Clin Endocrinol Metab. 2004;89:765–9.
39. Kadoglou NP, Vrabas IS, Kapelouzou A, et al. The impact of
aerobic exercise training on novel adipokines, apelin and ghrelin,
in patients with type 2 diabetes. Med Sci Monit. 2012;18:CR290–
5.
40. Quazi R, Palaniswamy C, Frishman WH. The emerging role
of apelin in cardiovascular disease and health. Cardiol Rev.
2009;17:283–6.
41. García EA, Korbonits M. Ghrelin and cardiovascular health. Curr
Opin Pharmacol. 2006;6:142–7.
42. Kadoglou NP, Sailer N, Moumtzouoglou A, et al. Visfatin
(nampt) and ghrelin as novel markers of carotid atherosclerosis
in patients with type 2 diabetes. Exp Clin Endocrinol Diabetes.
2010;118:75–80.
43. Bortolotto LA. Modifications of structural and functional proper-
ties of large arteries in diabetes mellitus. Arq Bras Endocrinol
Metab. 2007;51:176–84.
44. Christen AI, Armentano RL, Miranda A, et al. Arterial wall
structure and dynamics in type 2 diabetes mellitus methodologi-
cal aspects and pathophysiological findings. Curr Diabetes Rev.
2010;6:367–77.
45. Rizzoni D, Porteri E, Guelfi D, et al. Structural alterations in
subcutaneous small arteries of normotensive and hypertensive
patients with non-insulin-dependent diabetes mellitus. Circulation.
2001;103:1238–44.
46. Schofield I, Malik R, Izzard A, et al. Vascular structural and
functional changes in type 2 diabetes mellitus: evidence for the
roles of abnormal myogenic responsiveness and dyslipidemia.
Circulation. 2002;106:3037–43.
47. Agabiti Rosei E, Rizzoni D. Small artery remodelling in diabetes.
J Cell Mol Med. 2010;14:1030–6.
48. Katz PS, Trask AJ, Souza-Smith FM, et al. Coronary arterioles in
type 2 diabetic (db/db) mice undergo a distinct pattern of remod-
eling associated with decreased vessel stiffness. Basic Res
Cardiol. 2011;106:1123–34.
49. Souza-Smith FM, Katz PS, Trask AJ, et al. Mesenteric resistance
arteries in type 2 diabetic db/db mice undergo outward remodel-
ing. PLoS One. 2011;6:e23337.
50. •Trask AJ, Delbin MA, Katz PS, et al. Differential coronary
resistance microvessel remodeling between type 1 and type 2
diabetic mice: impact of exercise training. Vascul Pharmacol.
2012;57:187–93. This study demonstrates that the adverse re-
modeling of coronary microvessels in type 2 diabetes can be
improved by aerobic exercise training.
51. Kim SH, Lee SJ, Kang ES, et al. Effects of lifestyle modification on
metabolic parameters and carotid intima-media thickness in patients
with type 2 diabetes mellitus. Metabolism. 2006;55:1053–9.
52. Loimaala A, Groundstroem K, Rinne M, et al. Effect of long-term
endurance and strength training on metabolic control and arterial
elasticity in patients with type 2 diabetes mellitus. Am J Cardiol.
2009;103:972–7.
53. Samaranayake NR, Ong KL, Leung RY, et al. Management of
obesity in the National Health and Nutrition Examination Survey
(NHANES), 2007-2008. Ann Epidemiol. 2012;22:349–53.
54. Aghamohammadzadeh R, Heagerty AM. Obesity-related hyperten-
sion: epidemiology, pathophysiology, treatments, and the contribu-
tion of perivascular adipose tissue. Ann Med. 2012;44:S74–84.
55. Rizzoni D, De Ciuceis C, Porteri E, et al. Structural alterations in
small resistance arteries in obesity. Basic Clin Pharmacol Toxicol.
2012;110:56–62.
56. Weil BR, Stauffer BL, Mestek ML, et al. Influence of abdominal
obesity on vascular endothelial function in overweight/obese
adult men. Obesity (Silver Spring). 2011;19:1742–6.
57. Greenstein AS, Khavandi K, Withers SB, et al. Local inflamma-
tion and hypoxia abolish the protective anticontractile properties
of perivascular fat in obese patients. Circulation. 2009;119:1661–
70.
58. Okay DM, Jackson PV, Marcinkiewicz M, Papino MN. Exercise
and obesity. Prim Care. 2009;36:379–93.
59. Jakicic JM, Otto AD. Treatment and prevention of obesity: what
is the role of exercise? Nutr Rev. 2006;64:S57–61.
60. de Moraes C, Camargo EA, Antunes E, et al. Reactivity of mesen-
teric and aortic rings from trained rats fed with high caloric diet.
Comp Biochem Physiol A Mol Integr Physiol. 2007;147:788–92.
61. de Moraes C, Davel AP, Rossoni LV, et al. 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.
62. Bunker AK, Arce-Esquivel AA, Rector RS, et al. Physical
activity maintains aortic endothelium-dependent relaxation in
the obese type 2 diabetic OLETF rat. Am J Physiol Heart Circ
Physiol. 2010;298:H1889–901.
63. Mikus CR, Rector RS, Arce-Esquivel AA, et al. Daily physical
activity enhances reactivity to insulin in skeletal muscle arterioles
of hyperphagic Otsuka Long-Evans Tokushima Fatty rats. J Appl
Physiol. 2010;109:1203–10.
64. Sciacqua A, Candigliota M, Ceravolo R, et al. Weight loss in
combination with physical activity improves endothelial dysfunc-
tion in human obesity. Diabetes Care. 2003;26:1673–8.
65. Watts K, Beye P, Siafarikas A, et al. Exercise training normalizes
vascular dysfunction and improves central adiposity in obese
adolescents. J Am Coll Cardiol. 2004;43:1823–7.
66. Schjerve IE, Tyldum GA, Tjønna AE, et al. Both aerobic endur-
ance and strength training programmes improve cardiovascular
health in obese adults. Clin Sci (Lond). 2008;115:283–93.
67. Murphy EC, Carson L, Neal W, et al. Effects of an exercise
intervention using Dance Dance Revolution on endothelial func-
tion and other risk factors in overweight children. Int J Pediatr
Obes. 2009;4:205–14.
68. Miyaki A, Maeda S, Yoshizawa M, et al. Effect of habitual
aerobic exercise on body weight and arterial function in over-
weight and obese men. Am J Cardiol. 2009;104:823–8.
69. Mestek ML, Westby CM, Van Guilder GP, et al. Regular aerobic
exercise, without weight loss, improves endothelium-dependent
vasodilation in overweight and obese adults. Obesity (Silver
Spring). 2010;18:1667–9.
70. Vinet A, Karpoff L, Walther G, et al. Vascular reactivity at rest
and during exercise in middle-aged obese men: effects of
short-term, low-intensity, exercise training. Int J Obes (Lond).
2011;35:820–8.
71. Hanssen H, Nickel T, Drexel V, et al. Exercise-induced alterations
of retinal vessel diameters and cardiovascular risk reduction in
obesity. Atherosclerosis. 2011;216:433–9.
72. Lee MY, Griendling KK. Redox signaling, vascular function, and
hypertension. Antioxid Redox Signal. 2008;10:1045–59.
Curr Hypertens Rep
Author's personal copy
73. Briones AM, Touyz RM. Oxidative stress and hypertension:
current concepts. Curr Hypertens Rep. 2010;12:135–42.
74. Briones AM, Arribas SM, Salaices M. Role of extracellular
matrix in vascular remodeling of hypertension. Curr Opin
Nephrol Hypertens. 2010;19:187–94.
75. •• Ghiadoni L, Taddei S, Virdis A. Hypertension and endothelial
dysfunction: therapeutic approach. Curr Vasc Pharmacol.
2012;10:42–60. This is an interesting review focusing on endo-
thelial dysfunction in hypertension and in the effects of different
therapeutic approaches, in addition to demonstrating several
methodologies developed to evaluate endothelial dysfunction.
76. Mulvany MJ. Small artery remodeling in hypertension. Basic
Clin Pharmacol. 2012;110:49–55.
77. Félétou M, Huang Y, Vanhoutte PM. Endothelium-mediated
control of vascular tone: COX-1 and COX-2 products. Br J
Pharmacol. 2011;164:894–912.
78. •• Montezano AC, Touyz RM. Oxidative stress, Noxs, and hy-
pertension: experimental evidence and clinical controversies.
Ann Med. 2012;44:S2–16. The present review analyzes the
putative function of ROS in the pathogenesis of hypertension
and focuses on the role of Noxs in ROS generation.
79. Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the
Joint National Committee on Prevention, Detection, Evaluation, and
Treatment of High Blood Pressure. Hypertension. 2003;42:1206–52.
80. Pescatello LS, Franklin BA, Fagard R, et al. American College of
Sports Medicine position stand. Exercise and hypertension. Med
Sci Sports Exerc. 2004;36:533–53.
81. Barlow CE, LaMonte MJ, Fitzgerald SJ, et al. Cardiorespiratory
fitness is an independent predictor of hypertension incidence
among initially normotensive healthy women. Am J Epidemiol.
2006;163:142–50.
82. Rankinen T, Church TS, Rice T, et al. Cardiorespiratory fitness,
BMI, and risk of hypertension: the HYPGENE study. Med Sci
Sports Exerc. 2007;39:1687–92.
83. Shook RP, Lee DC, Sui X, et al. Cardiorespiratory fitness reduces
the risk of incident hypertension associated with a parental his-
tory of hypertension. Hypertension. 2012;59:1220–4.
84. Cardoso Jr CG, Gomides RS, Queiroz AC, et al. Acute and
chronic effects of aerobic and resistance exercise on ambulatory
blood pressure. Clinics (Sao Paulo). 2010;65:317–25.
85. Cornelissen VA, Fagard RH. Effects of endurance training on
blood pressure, blood pressure-regulating mechanisms, and car-
diovascular risk factors. Hypertension. 2005;46:667–75.
86. Fagard RH. Exercise is good for your blood pressure: effects of
endurance training and resistance training. Clin Exp Pharmacol
Physiol. 2006;33:853–6.
87. Joyner MJ, Green DJ. Exercise protects the cardiovascular system:
effects beyond traditional risk factors. J Physiol. 2009;587:5551–8.
88. Roque FR, Briones AM, García-Redondo AB, et al. Aerobic
exercise reduces oxidative stress and improves vascular changes
of small mesenteric and coronary arteries in hypertension. Br J
Pharmacol. 2013;168:686–703.
89. Fagard RH, Cornelissen VA. Effect of exercise on blood pressure
control in hypertensive patients. Eur J Cardiovasc Prev Rehabil.
2007;14:12–7.
90. •Nualnim N, Parkhurst K, Dhindsa M, Tarumi T, Vavrek J,
Tanaka H. Effects of swimming training on blood pressure and
vascular function in adults >50 years of age. Am J Cardiol.
2012;109:1005–10. This study demonstrates for the first time that
swimming training also improves vascular function and arterial
stiffness in prehypertensive or stage 1 hypertensive adults.
91. Schulze PC. Beneficial effects of moderate exercise in arterial
hypertension. Hypertension. 2009;53:600–1.
92. Kuru O, Sentürk UK, Koçer G, et al. Effect of exercise training
on resistance arteries in rats with chronic NOS inhibition. J Appl
Physiol. 2009;107:896–902.
93. Higashi Y, Yoshizumi M. Exercise and endothelial function: role
of endothelium-derived nitric oxide and oxidative stress in
healthy subjects and hypertensive patients. Pharmacol Ther.
2004;102:87–96.
94. Jasperse JL, Laughlin MH. Endothelial function and exercise
training: evidence from studies using animal models. Med Sci
Sports Exerc. 2006;38:445–54.
95. McAllister RM, Newcomer SC, Laughlin MH. Vascular nitric
oxide: effects of exercise training in animals. Appl Physiol Nutr
Metab. 2008;33:173–8.
96. •• Gomes EC, Silva AN, de Oliveira MR. Oxidants, antioxidants,
and the beneficial roles of exercise-induced production of reac-
tive species. Oxid Med Cell Longev. 2012. doi:10.1155/2012/
756132.This is an excellent overview of the influence of exercise
producing reactive oxygen species and their adaptive responses
to training.
97. Kimura H, Kon N, Furukawa S, et al. Effect of endurance exer-
cise training on oxidative stress in spontaneously hypertensive
rats (SHR) after emergence of hypertension. Clin Exp Hypertens.
2010;32:407–15.
98. Yang AL, Yeh CK, Su CT, et al. Aerobic exercise acutely im-
proves insulin- and insulin-like growth factor-1-mediated vasore-
laxation in hypertensive rats. Exp Physiol. 2010;95:622–9.
99. Yang AL, Lo CW, Lee JT, Su CT. Enhancement of vasorelaxation
in hypertension following high-intensity exercise. Chin J Physiol.
2011;54:87–95.
100. Faria Tde O, Targueta GP, Angeli JK, et al. Acute resistance
exercise reduces blood pressure and vascular reactivity, and in-
creases endothelium-dependent relaxation in spontaneously hy-
pertensive rats. Eur J Appl Physiol. 2010;110:359–66.
101. Silva DM, Gomes-Filho A, Olivon VC, et al. Swimming training
improves the vasodilator effect of angiotensin-(1-7) in the aorta of
spontaneously hypertensive rat. J Appl Physiol. 2011;111:1272–
7.
102. Hellsten Y, Jensen L, Thaning P, et al. Impaired formation of
vasodilators in peripheral tissue in essential hypertension is nor-
malized by exercise training: role of adenosine and prostacyclin. J
Hypertens. 2012;30:2007–14.
103. Hanse n AH, N yberg M, Ba ngsbo J, et al. Exerc ise t raining
alters the balance between vasoactive compounds in skel-
etal muscle of individuals with essential hypertension.
Hypertension. 2011;58:943–9.
104. Mancia G, De Backer G, Dominiczak A, et al. 2007 Guidelines
for the management of arterial hypertension: the Task Force for
the Management of Arterial Hypertension of the European
Society of Hypertension (ESH) and of the European Society of
Cardiology (ESC). Eur Heart J. 2007;28:1462–536.
105. Guimarães GV, Ciolac EG, Carvalho VO, et al. Effects of
continuous vs. interval exercise training on blood pressure and
arterial stiffness in treated hypertension. Hypertens Res.
2010;33:627–32.
106. Goldberg MJ, Boutcher SH, Boutcher YN. The effect of 4 weeks
of aerobic exercise on vascular and baroreflex function of young
men with a family history of hypertension. J Hum Hypertens.
2012;26:644–9.
107. Moraes-Teixeira Jde A, Félix A, Fernandes-Santos C, et al.
Exercise training enhances elastin, fibrillin and nitric oxide in
the aorta wall of spontaneously hypertensive rats. Exp Mol
Pathol. 2010;89:351–7.
108. Jordão MT, Ladd FV, Coppi AA, et al. Exercise training restores
hypertension-induced changes in the elastic tissue of the thoracic
aorta. J Vasc Res. 2011;48:513–24.
109. Amaral SL, Zorn TM, Michelini LC. Exercise training normalizes
wall-to-lumen ratio of the gracilis muscle arterioles and reduces
pressure in spontaneously hypertensive rats. J Hypertens.
2000;18:1563–72.
Curr Hypertens Rep
Author's personal copy
110. Melo RM, Martinho Jr E, Michelini LC. Training-induced,
pressure-lowering effect in SHR: wide effects on circulatory
profile of exercised and nonexercised muscles. Hypertension.
2003;42:851–7.
111. Rossoni LV, Oliveira RA, Caffaro RR, et al. Cardiac benefits of
exercise training in aging spontaneously hypertensive rats. J
Hypertens. 2011;29:2349–58.
112. •Fernandes T, Magalhães FC, Roque FR, et al. Exercise
training prevents the microvascular rarefaction in hyperten-
sion balancing angiogenic and apoptotic factors: role of
microRNAs-16, -21, and -126. Hypertension. 2012;59:513–
20. This study demonstrates that exercise training prevents
the microvascular rarefaction in hypertension through a
pathway involving MicroRNAs.
113. Fernandes T, Nakamuta JS, Magalhães FC, et al. Exercise training
restores the endothelial progenitor cells number and function in
hypertension: implications for angiogenesis. J Hypertens.
2012;30:2133–43.
114. Alberti KG, Eckel RH, Grundy SM, et al. Harmonizing the
metabolic syndrome: a joint interim statement of the International
Diabetes Federation Task Force on Epidemiology and Preven-
tion; National Heart, Lung, and Blood Institute; American Heart
Association; World Heart Federation; International Atherosclero-
sis Society; and International Association for the Study of
Obesity. Circulation. 2009;120:1640–5.
115. Tziomalos K, Athyros VG, Karagiannis A, et al. Endothelial
dysfunction in metabolic syndrome: prevalence, pathogenesis
and management. Nutr Metab Cardiovasc Dis. 2010;20:140–
6.
116. Martín-Cordero L, García JJ, Hinchado MD, et al. The
interleukin-6 and noradrenaline mediated inflammation-stress
feedback mechanism is dysregulated in metabolic syndrome:
effect of exercise. Cardiovasc Diabetol. 2011;10:42.
117. •• Golbidi S, Mesdaghinia A, Golbidi S, Mesdaghinia A, Laher I.
Exercise in the metabolic syndrome. Oxid Med Cell Longev.
2012. doi:10.1155/2012/349710.This is an interesting review
that discusses the role of oxidative stress and consequent inflam-
mation related to metabolic syndrome and the impact of exercise
on these pathophysiological pathways.
118. Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and
management of the metabolic syndrome: an American Heart
Association/National Heart, Lung, and Blood Institute Scientific
Statement. Circulation. 2005;112:2735–52.
119. Stensvold D, Tjønna AE, Skaug EA, et al. Strength training
versus aerobic interval training to modify risk factors of metabolic
syndrome. J Appl Physiol. 2010;108:804–10.
120. Tjønna AE, Lee SJ, Rognmo Ø, et al. Aerobic interval training
versus continuous moderate exercise as a treatment for the met-
abolic syndrome: a pilot study. Circulation. 2008;118:346–54.
121. Seligman BG, Polanczyk CA, Santos AS, et al. Intensive practi-
cal lifestyle intervention improves endothelial function in meta-
bolic syndrome independent of weight loss: a randomized
controlled trial. Metabolism. 2011;60:1736–40.
122. •da Silva CA, Ribeiro JP, Canto JC, et al. High-intensity aerobic
training improves endothelium-dependent vasodilation in patients
with metabolic syndrome and type 2 diabetes mellitus. Diabetes
Res Clin Pract. 2012;95:237–45. This study compares the effect
of low intensity and high intensity aerobic training on
endothelium-dependent vasodilation in patients with metabolic
syndrome and T2DM.
123. Johnson JL, Slentz CA, Houmard JA, et al. Exercise training
amount and intensity effects on metabolic syndrome (from
Studies of a Targeted Risk Reduction Intervention through
Defined Exercise). Am J Cardiol. 2007;100:1759–66.
124. Lavrencic A, Salobir BG, Keber I. Physical training improves
flow-mediated dilation in patients with the polymetabolic syn-
drome. Arterioscler Thromb Vasc Biol. 2000;20:551–5.
125. Arvola P, Wu X, Kähönen M, et al. Exercise enhances vasorelax-
ation in experimental obesity associated hypertension. Cardiovasc
Res. 1999;43:992–1002.
126. 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:R987–91.
127. Sebai M, Lu S, Xiang L, et al. Improved functional vasodilation
in obese Zucker rats following exercise training. Am J Physiol
Heart Circ Physiol. 2011;301:H1090–6.
128. Xiang L, Dearman J, Abram SR, et al. Insulin resistance and
impaired functional vasodilation in obese Zucker rats. Am J
Physiol Heart Circ Physiol. 2008;294:H1658–66.
129. Jae SY, Heffernan KS, Fernhall B, et al. Association between
cardiorespiratory fitness and arterial stiffness in men with the
metabolic syndrome. Diabetes Res Clin Pract. 2010;90:326–32.
130. Madden KM, Lockhart C, Cuff D, et al. Short-term aerobic
exercise reduces arterial stiffness in older adults with type 2
diabetes, hypertension, and hypercholesterolemia. Diabetes
Care. 2009;32:1531–5.
Curr Hypertens Rep
Author's personal copy
