cells

Review
Training the Vessels: Molecular and Clinical Effects of Exercise
on Vascular Health—A Narrative Review
Karsten Königstein 1, * , Konstantina Dipla 2, * and Andreas Zafeiridis 2

1 Department of Sport, Exercise and Health, Division Sports and Exercise Medicine, University of Basel,
4052 Basel, Switzerland
2 Laboratory of Exercise Physiology and Biochemistry, Department of Physical Education and Sports Science at
Serres, Aristotle University of Thessaloniki, 62100 Serres, Greece; [email protected]
* Correspondence: [email protected] (K.K.); [email protected] (K.D.); Tel.: +41-61-2074741 (K.K.);
+30-2310-991087 (K.D.)

Abstract: Accelerated biological vascular ageing is still a major driver of the increasing burden
of cardiovascular disease and mortality. Exercise training delays this process, known as early
vascular ageing, but often lacks effectiveness due to a lack of understanding of molecular and clinical
adaptations to specific stimuli. This narrative review summarizes the current knowledge about
the molecular and clinical vascular adaptations to acute and chronic exercise. It further addresses
how training characteristics (frequency, intensity, volume, and type) may influence these processes.
Finally, practical recommendations are given for exercise training to maintain and improve vascular
health. Exercise increases shear stress on the vascular wall and stimulates the endothelial release of
circulating growth factors and of exerkines from the skeletal muscle and other organs. As a result,
remodeling within the vascular walls leads to a better vasodilator and -constrictor responsiveness,
reduced arterial stiffness, arterio- and angiogenesis, higher antioxidative capacities, and reduced
oxidative stress. Although current evidence about specific aspects of exercise training, such as F-I-T-T,
is limited, and exact training recommendations cannot be given, some practical implications can be
extracted. As such, repeated stimuli 5–7 days per week might be necessary to use the full potential
of these favorable physiological alterations, and the cumulative volume of mechanical shear stress
seems more important than peak shear stress. Because of distinct short- and long-term effects of
resistance and aerobic exercise, including higher and moderate intensities, both types of exercise
Citation: Königstein, K.; Dipla, K.;
should be implemented in a comprehensive training regimen. As vascular adaptability towards
Zafeiridis, A. Training the Vessels:
exercise remains high at any age in both healthy individuals and patients with cardiovascular diseases,
Molecular and Clinical Effects of
individualized exercise-based vascular health prevention should be implemented in any age group
Exercise on Vascular Health—A
Narrative Review. Cells 2023, 12, 2544.
from children to centenarians.
https://doi.org/10.3390/
cells12212544 Keywords: exercise; hypertension; blood pressure; cardiovascular disease; microvascular function;
exercise prescription
Academic Editor: Robert Wessells

Received: 19 September 2023

Revised: 27 October 2023
Accepted: 28 October 2023 1. Background
Published: 30 October 2023
Accelerated biological vascular ageing (early vascular ageing) leads to early target
organ damage and subsequently to diseases, such as atherosclerosis, chronic kidney disease,
degenerative brain disease, and retinopathy [1]. The prevalence of early vascular ageing in
Copyright: © 2023 by the authors.
a population, i.e., defined as aortic pulse wave velocity >90th percentile, can be as high as
Licensee MDPI, Basel, Switzerland. 37% [2], which is why the maintenance of optimal vascular health throughout the entire
This article is an open access article lifespan is already accepted as a main goal of preventive health care [3]. Regular physical
distributed under the terms and activity and exercise can effectively attenuate the progression of early vascular ageing and
conditions of the Creative Commons should therefore be part of any treatment efforts aiming to improve vascular and general
Attribution (CC BY) license (https:// health [4,5]. However, the effectiveness of exercise interventions on biomarkers of vascular
creativecommons.org/licenses/by/ health is often limited and not sustainable in the long-term after the discontinuation of
4.0/). exercise training. Targeted exercise, based on objective and subjective individual criteria,

Cells 2023, 12, 2544. https://doi.org/10.3390/cells12212544 https://www.mdpi.com/journal/cells

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discontinuation
carries of exercise
the potential training.
to overcome Targeted
these exercise,
limitations [6,7].based on objective
Accordingly, andunderstanding
a better subjective
individual criteria, carries the potential to overcome these limitations [6,7].
of the molecular mechanisms underlying the acute responses and long-term adaptations of Accordingly,
a better
the understanding
vascular of the molecular
organ to exercise will leadmechanisms
to the design underlying the acuteexercise
of more effective responses and
programs,
long-term adaptations of the vascular organ to exercise will lead to the design
with better adherence by participants to lifelong training, and potentially will result in of more
effective exercise programs, with better adherence by participants to lifelong training, and
a better clinical outcome. Acute hemodynamic adaptations to exercise lead to changes
potentially will result in a better clinical outcome. Acute hemodynamic adaptations to ex-
in both endothelial and vascular smooth muscle cell function. Regular exercise training
ercise lead to changes in both endothelial and vascular smooth muscle cell function. Reg-
improves nitric oxide (NO) availability and reduces vascular oxidative stress [8]. As
ular exercise training improves nitric oxide (NO) availability and reduces vascular oxida-
a result, endothelial vasodilator and -constrictor responsiveness as well as pulse wave
tive stress [8]. As a result, endothelial vasodilator and -constrictor responsiveness as well
velocity and arterial stiffness are improved [9]. In addition, exercise induces vascular
as pulse wave velocity and arterial stiffness are improved [9]. In addition, exercise induces
structural adaptations and stimulates angiogenesis and arteriogenesis. This narrative
vascular structural adaptations and stimulates angiogenesis and arteriogenesis. This nar-
review summarizes current knowledge about the acute molecular responses to exercise
rative review summarizes current knowledge about the acute molecular responses to ex-
within the
ercise withinendothelial and smooth
the endothelial and smoothmuscle cells
muscle of of
cells thethe
vascular
vascularwall
walland
and the
the associated
associ-
acute and chronic clinical vascular adaptations. It further addresses how
ated acute and chronic clinical vascular adaptations. It further addresses how trainingtraining frequency,
fre-
intensity, volume, volume,
quency, intensity, and typeand influence these processes.
type influence Finally, Finally,
these processes. practicalpractical
recommendations
recom-
are given forare
mendations exercise training
given for exerciseto maintain
training toand improve
maintain andvascular
improvehealth.
vascular health.
2.
2. Acute MolecularEffects
Acute Molecular EffectsofofExercise
Exercise onon Blood
Blood Vessels
Vessels
During exercise,the
During exercise, theincreased
increasedbloodblood flow
flow stresses
stresses thethe vasculature
vasculature andand increases
increases lu- lu-
minal shear stress. In turn, shear stress causes the deformation of glycocalyx
minal shear stress. In turn, shear stress causes the deformation of glycocalyx receptors on receptors
on
thethe lumen
lumen of endothelial
of endothelial cells,
cells, activating
activating calcium
calcium channels.
channels. Calcium
Calcium signaling
signaling leadsleads
to to
prostaglandin releaseand
prostaglandin release andconsequently
consequently induces
induces cyclic
cyclic adenosine
adenosine monophosphate
monophosphate medi- medi-
ated
ated smooth musclerelaxation.
smooth muscle relaxation.Luminal
Luminal shear
shear stress
stress activates
activates protein
protein kinase
kinase B, inducing
B, inducing
endothelial NO synthase
endothelial NO synthasephosphorylation
phosphorylationand andconsequently
consequently NONO release.
release. NONO interacts
interacts
with
with guanylate cyclase,
cyclase,activating
activatinga acascade
cascade ofof molecular
molecular signaling
signaling which
which leads
leads to reduced
to reduced
intracellular
intracellular calcium and increased
increased intracellular
intracellularpotassium,
potassium,favoring
favoringcell
cellmembrane
membranehy- hyper-
polarization andand
perpolarization smooth
smooth muscle
musclerelaxation.
relaxation. InIn
addition,
addition,when
whenNONOdiffuses
diffusestotothe theluminal
lu-
side
minalofside
the endothelial layer, layer,
of the endothelial it alsoitexerts an antithrombotic
also exerts action
an antithrombotic by inhibiting
action by inhibiting platelet
adhesion and aggregation
platelet adhesion [10] (Figure
and aggregation 1).
[10] (Figure 1).

Figure 1.
Figure 1. Acute
Acute molecular
moleculareffects
effectsofofexercise
exerciseononblood
blood vessels. During
vessels. exercise,
During increased
exercise, arterial
increased arterial
blood flow leads to an elevation of blood pressure (greater hydrostatic pressure), luminal shear
blood flow leads to an elevation of blood pressure (greater hydrostatic pressure), luminal shear stress,
stress, and arterial wall stress. The consequence is a vasodilation predominantly in the resistance
and arterial wall stress. The consequence is a vasodilation predominantly in the resistance arteries
arteries (mainly due to a greater release of nitric oxide (NO) and prostacyclin (PGI2) from the endo-
(mainly dueand
thelial cells to adilation
greaterofrelease of nitric
the smooth oxide
muscle (NO)
cells). and prostacyclin
In addition, (PGI2)changes
during exercise, from the in endothelial
neural,
cells and dilation
metabolic, of thefactors
and humoral smooth muscle
take place cells).
in both Intheaddition, during
micro- and exercise, changes
macrovascular in All
circulation. neural,
these changes
metabolic, andcontribute to acutetake
humoral factors adaptations
place in in arterial
both function,
the micro- anddiameter, and wall
macrovascular thickness. All
circulation. NO:these
changes contribute to acute adaptations in arterial function, diameter, and wall thickness. NO: nitric
oxide, PGI2: prostacyclin I2, NPY: neuropeptide Y, GABA: Gamma-aminobutyric acid, ATP/AMP:
Adenosine triphosphate/Adenosine monophosphate; [Ca2+ ]: intracellular calcium.
Cells 2023, 12, x FOR PEER REVIEW 3 of 15

nitric oxide, PGI2: prostacyclin I2, NPY: neuropeptide Y, GABA: Gamma-aminobutyric acid,
Cells 2023, 12, 2544 3 of 15
ATP/AMP: Adenosine triphosphate/Adenosine monophosphate; [Ca2+]: intracellular calcium.

Acute bouts of exercise also enhance proangiogenic stimuli, such as the vascular en-
Acutegrowth
dothelial bouts of exercise
factor alsowhich
(VEGF), enhance proangiogenic
in turn stimuli,
signals capillary such as the vascular
development. Previous
endothelial
studies havegrowth shownfactor
VEGF(VEGF),
increaseswhich in turn to
in response signals capillary
a single exercise development.
bout [11]. The Previous
level of
studies
hypoxiahave seemsshown VEGF increases
to upregulate the VEGFin response
response to[12,13].
a singleOn
exercise
the otherbouthand,
[11]. The
acutelevel of
bouts
hypoxia
of exercise seems
alsotoincrease
upregulate the VEGF
the release response [12,13].
of angiostatic factorsOn the other
(factors thathand, acute
prevent bouts of
angiogene-
exercise
sis) suchalso increase theand
as angiostatin release of angiostatic
platelet factorsAlthough
factor 4 (PF-4). (factors that
there prevent angiogenesis)
is a concomitant in-
such
crease in opposing angiogenic and angiostatic factors during an acute bout of increase
as angiostatin and platelet factor 4 (PF-4). Although there is a concomitant exercise,
in opposing
repeated angiogenic
exercise stimuli and angiostatic
lead factors
to a decrease during
in the an acute
angiostatic bout of
factors, exercise, the
increasing repeated
abun-
exercise
dance ofstimuli lead factors,
angiogenic to a decrease in theangiogenesis
promoting angiostatic factors,
(Figureincreasing
1). the abundance of
angiogenic factors, promoting angiogenesis (Figure 1).
3. Chronic Adaptations of Blood Vessels to Exercise
3. Chronic Adaptations of Blood Vessels to Exercise
3.1. Long-Term Structural and Functional Vascular Adaptations in Response to Regular Exercise
3.1. Long-Term Structural and Functional Vascular Adaptations in Response to Regular
TrainingTraining
Exercise
ItIt is
is well
well established
established that
that regular
regular exercise
exercise training
training improves
improves vascular
vascular function
function inin both
both
health and
health and disease.
disease. Chronic
Chronictraining-related
training-related adaptations
adaptations of of
thethe
cardiovascular
cardiovascular system im-
system
prove tissue perfusion and nutrient exchange at rest and result in
improve tissue perfusion and nutrient exchange at rest and result in a greater capacity to a greater capacity to
increase them during exercise. In this context, both structural and functional
increase them during exercise. In this context, both structural and functional adaptations of adaptations
of the
the bloodblood vessels
vessels havehave been
been reported
reported (Figure
(Figure 2). 2).

Figure 2.2. Chronic

Figure Chronic adaptations
adaptations of
ofblood
bloodvessels
vesselsto
toexercise.
exercise. Repeated
Repeated hemodynamic
hemodynamic stimuli
stimuli due
due to
to
regular exercise training can lead to better compliance and regulation of blood pressure
regular exercise training can lead to better compliance and regulation of blood pressure in conduit in conduit
arteries as well as in the small vessels. In addition, the vascular adaptations lead to a better capacity
arteries as well as in the small vessels. In addition, the vascular adaptations lead to a better capacity
for oxygen delivery and diffusion from the capillaries to the skeletal muscle cells and possibly con-
for oxygen delivery and diffusion from the capillaries to the skeletal muscle cells and possibly
tribute to improvements in exercise capacity. Regular exercise can prevent and/or reverse age-re-
contribute to improvements
lated endothelial dysfunctionininexercise
both thecapacity. Regular
macro- and exercise can
microvascular prevent and/or
circulation reverseNitric
by increasing age-
related endothelial dysfunction in both the macro- and microvascular circulation by increasing
oxide (NO) bioavailability, improving intracellular redox balance and mitochondrial health, and Nitric
oxide (NO)
lowering bioavailability,
systemic improving
inflammation. intracellular
Overall, redox balance
these adaptations and mitochondrial
can reduce health,
the atherosclerotic and
burden
lowering systemic
in large vessels inflammation.
and Overall,
favorably alter these adaptations
the microvascular can reduce
function the atherosclerotic
in healthy individuals andburden in
in indi-
viduals with cardiovascular disease. GLUT4: Glucose transporter type 4
large vessels and favorably alter the microvascular function in healthy individuals and in individuals
with cardiovascular disease. GLUT4: Glucose transporter type 4.
Briefly, exercise stimulates angiogenesis, the formation of capillary networks, and
Briefly, exercise
arteriogenesis, stimulates
the growth angiogenesis,
of preexistent the formation
collateral of capillary
arterioles. networks,
Early reports showed anda
arteriogenesis, the growth of preexistent collateral arterioles. Early reports showed
greater arteriolar and capillary density in trained individuals compared to untrained a greater
arteriolar and capillary
aged-matched controlsdensity
[14]. Aninincrease
trained individuals
in capillarycompared
density intoresponse
untrained
to aged-matched
exercise train-
controls [14]. been
ing has also An increase
reportedinin
capillary
healthydensity in response
individuals as welltoasexercise
in thosetraining has also
with chronic been
disease
reported in healthy individuals as well as in those with chronic disease [15]. Adaptations
seem to be dependent on the fiber type and the individual’s training status. Specifically,
although skeletal muscles containing mostly slow-twitch oxidative fibers have a greater
Cells 2023, 12, 2544 4 of 15

capillary density [14], fast oxidative–glycolytic and fast–glycolytic muscle fibers appear to
exhibit a greater increase in arteriolar density in response to training [15]. Recent evidence
suggests that stimulating angiogenesis promotes healthy ageing and extends life span [16].
However, while in animal models angiogenesis can be evident after a few repeated bouts
of exercise, in humans, this process might take weeks to months of regular training [17].
Studies have also suggested that repeatedly elevated shear stress, as it may occur
during exercise training, induces increases in the arterial luminal diameter [18]. In de-
tail, larger conduit arteries (increased conduit artery size in epicardial arteries and those
supplying skeletal muscle) were reported in athletes compared to untrained healthy in-
dividuals [19]. Between-limb studies in athletes demonstrated higher arterial diameters
and lower arterial wall thickness in the predominantly used limbs (carotid, femoral, and
popliteal and brachial intima-media thickness) [18,20,21]. As a result, peak limb blood flow
responses were found to be enhanced also in comparison with nonathletes, suggesting
greater vasodilator reserves in athletes and trained individuals [19].
Functional vascular adaptations in response to exercise training are also evident in
healthy individuals and in individuals with chronic diseases [17,22]. Alterations in the
arterial tone and reductions in resting blood pressure are the results of a complex inter-
play of humoral, paracrine, and neural mechanisms, in which a higher bioavailability of
endothelial NO as well as transiently higher levels of vascular and interstitial cell adhesion
molecules, endothelin-1, and reactive oxygen species mediate the exercise stimulus. Fur-
thermore, some studies reported that in individuals with vascular dysfunction (older adults,
hypertensives), exercise training potentiate the release of NO-independent vasodilator sub-
stances such as prostacyclin I2 (in muscle and interstitial tissue) and adenosine (interstitial
tissue) and to reduces vasoconstrictors such as endothelin-1 and angiotensin II [23,24].
In addition, exercise improves endothelial function through enhancing endothelial cell
proliferation, inhibiting apoptosis, and mobilizing endothelial progenitor cells [25].
Collectively, all these adaptations improve constriction and dilatation responses of the
vascular smooth muscle cells to vasoactive factors, increase arterial compliance, and reduce
the probability of flow-limiting stenosis when cardiovascular and/or metabolic disease
are present. Exercise also increases the content of collagen and elastin of atherosclerotic
plaques stabilizing plaque lesions and attenuating vascular stiffening/calcification.
In addition to these macrovascular effects of exercise, exerkines (signaling molecules
such as proteins, metabolites, and extracellular vesicles) are released in response to acute
and/or chronic exercise from the working skeletal muscle and the cardiometabolic, nervous,
and immune systems and induce adaptations in the microvascular system [26]. For example,
skeletal muscular VEGF and angiopoietin 1 enhance neovascularization and angiogenesis.
Further exerkine-related vascular effects are improved blood flow, endothelial function,
and blood pressure.

3.2. The Role of Mitochondria in Exercise-Induced Vascular Benefits

An increasing amount of evidence suggests a critical role of mitochondria in the
exercise-induced benefits on the vascular smooth muscle cells. However, direct evidence
is sparse and most of the available evidence is extrapolated from observation in cardiac
and skeletal myocytes [27]. Mitochondria are sophisticated and dynamically responsive
organelles involved in energy production, redox balance, signal transduction, apoptosis
(programmed cell death), and many other biological processes. Interestingly, cardiac
mitochondria are different from vascular mitochondria in terms of morphology, function,
and regulation. In cardiomyocytes, mitochondria comprise ~35% of the cell volume due
to the high metabolic demand and oxidative capacity of the cardiac muscle. However,
mitochondria in the vascular wall, mainly smooth muscle cells, comprise only ~2–5% of the
tissue volume since these cells exhibit high glycolytic rates even under well-oxygenated
conditions [28].
Exercise-induced adaptations involve improved mitochondrial biogenesis, signaling
transduction, respiratory function, and reduced chronic oxidative stress [29]. Additionally,
Cells 2023, 12, 2544 5 of 15

the de novo mitochondria combine their membranes with existing mitochondria (fusion), fa-
cilitating the distribution of metabolites, proteins, mtDNA, and other molecules to increase
the capacity of ATP synthesis and improve the oxidative processes. By the process of fission,
damaged areas of mitochondria are removed, and metabolic homeostasis is maintained.
Exercise promotes the degradation of damaged mitochondria via mitophagy [30,31].
Mitophagy is of great importance for the maintenance of vascular health since a growing
body of evidence suggests an involvement of impaired mitophagy to the pathogenesis of
vascular disease and the ageing process [29,32]. Specifically, an imbalance in the mitochon-
drial dynamics results in vascular dysfunction, as shown in perturbations that increase
fission or decrease fusion [33,34]. Furthermore, mitochondrial fragmentation and respi-
ratory chain dysfunction, driven by an altered activity of the GTPase dynamin-related
protein-1, might contribute to vascular dysfunction [34]. A previous study showed that
aerobic exercise training decreased dynamin-related protein-1 phosphorylation and in-
creased fat oxidation and insulin sensitivity in obese insulin-resistant adults, suggesting
that lifestyle-mediated improvements in substrate metabolism may be regulated through
the decreased activation of the dynamin-related protein-1 [35].
In summary, chronic exercise improves mitochondrial content and dynamics, resulting
in a better oxidative capacity. Although acute exercise bouts upregulate ROS generation,
chronic regular exercise results in lower chronic oxidative stress and less inflammation.

4. Clinical Vascular Effects of Exercise

4.1. Effects of Exercise on Vascular Health
Regular exercise reduces the risk of cardiovascular morbidity and mortality by up to
44% [36], delays all-cause mortality [37], and increases health span [38]. Surprisingly, less
than 50% of this effect is explained by reduced oxidative stress and subclinical inflammation
due to modifications in cardiovascular risk factors, such as blood pressure, insulin sensi-
tivity, blood lipids, and body composition [39]. The remaining gap in explaining vascular
benefits of exercise is likely to be filled by direct effects of exercise on the vascular wall
that translate into higher nitric oxide availability and favorable structural remodeling [18].
The result is a delayed progression of endothelial dysfunction and arterial stiffening with
ageing. This assumption is supported by a considerable body of evidence indicating a
positive association of cardiorespiratory fitness with endothelial function [40,41] and a
negative association of time spent exercising with arterial stiffness [42] as well as with wall
thickness [43]. Furthermore, longitudinal studies have shown an attenuated decline of
endothelial function with lifelong regular aerobic exercise until old age [5,44].

4.2. Clinical Vascular Effects of Short-Versus Long-Term Exercise

The extent and clinical relevance of vascular effects induced by single bouts of exercise
and short-term interventions are idiosyncratic in a way. Although endothelial function
appears to be modifiable within a few weeks of regular exercise [45], arterial stiffness and
structural integrity of the vascular wall improve either slowly or not at all [46,47]. This is
not in contrast to the consistent observations about beneficial vascular effects induced by
long-term exposure to regular exercise but rather indicates the complexity of the under-
lying mechanisms. Therefore, the prediction of exercise-related improvements of future
cardiovascular risk based on single biomarkers is limited, and therapeutic consequences
should be drawn with caution.

4.2.1. Influence of Age

Cardiovascular effects of chronic regular exercise are independent of sex and age [4,40]
and are already apparent in minors and young adults [48], as demonstrated by the European
Youth Heart Study [49] and the KiGGS study [50]. Considering the increasing prevalence
of obesity and inactivity among children and adolescents [51], preventive efforts involving
regular exercise should include the youngest individuals within a population. Additionally,
facing the lack of an extended health span along with an increasing life expectancy, it is
Cells 2023, 12, 2544 6 of 15

noteworthy that vascular adaptability towards exercise remains high until old age [52].
Thus, even the oldest individuals will considerably benefit from regular exercise, even if
they have never exercised before.

4.2.2. Influence of Cardiovascular Risk Factors and Diseases

Similar observations regarding clinical vascular effects of exercise have been made for
both healthy individuals and patients with comorbidities, such as metabolic syndrome [40],
arterial hypertension [53], and heart failure [40,54]. In contrast, exercise studies in ani-
mals provided evidence indicating an impaired mechanical transduction of elevated shear
stress [55] and an attenuated increase in nitric oxide release [56] in the presence of cardio-
vascular risk factors such as arterial hypertension. As an example, the exercise-induced
release of VEGF was attenuated in individuals with arterial hypertension, suggesting a
blunted neocapillarization following exercise training [57]. Furthermore, microvascular
dysfunction and reduced skeletal muscle oxygenation were associated with an exaggerated
blood pressure response during exercise in newly diagnosed, untreated hypertensive indi-
viduals [58]. Nonetheless, vascular function in patients with cardiovascular risk factors or
diseases remains highly adaptive to exercise, whereas structural vascular adaptations in the
macrovascular system might be less likely to occur, compared to healthy individuals [59].

4.2.3. Influence of Training Status and Physical Fitness Level

It is an appealing thought that cardiorespiratory fitness or previous training level
influence the vascular adaptability to an exercise stimulus. It seems only logical that a
highly trained organism does not have much room for further optimizations. Studies about
endothelial adaptations to exercise in highly trained athletes support this in part, as some
of them report better endothelial function than in untrained individuals [60–62], whereas
many others report no differences or even lower function [63–65]. However, studies that
compare vascular adaptations to exercise between trained versus untrained individuals are
lacking. Furthermore, the interrelation of local structural and functional properties of the
vascular wall is likely to be highly dynamic and influenced by training volume, intensity,
or other factors [66]. Accordingly, endothelial adaptations to exercise in elite athletes may
be highly dynamic and related to periodic variations of intensity, volume, frequency, and
type of training during their season [40,65,67].

5. Exercise Training to Improve Vascular Fitness

5.1. General Aspects of Exercise Training to Improve Vascular Health
The World Health Organization recommends at least 75 min per week of vigorous
physical activity or 150 min of moderate intensity [68]. The relationship between exercise
and cardiovascular risk has been described in a curvilinear dose–response pattern [69],
and numerous studies have consistently reported beneficial vascular effects of exercise
training [5,42–44,59,70]. However, these effects depend on frequency, intensity, volume,
and modality of the training, and are subject to considerable individual variation [71]. The
F(requency)-I(ntensity)-T(ime)-T(ype) principle provides a practical approach to structure
and adapt the training program according to the individual’s vascular responses (Figure 3).
 Cells 2023,
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Figure
Figure 3.3.Principles
Figure3.
3. Principles
Principles
Principles Figure 3. Principles
ofexercise
of exercise
exercise of exercise
training
training to training
improve
toimprove
improve to improve
vascular
vascular vascular
fitness.
fitness. The fitness.principle
F-I-T-T
TheF-I-T-T
The F-I-T-T
F-I-T-T The F-I-T-T
principle
principle principle (frequen
(frequency,
(frequency,
(frequency,
Figure of training to vascular fitness. The principle (frequency,
intensity, time,
intensity,time, intensity,
type)
time,type)
type)provides time,
provides type) provides
providesaaaapractical
practical a practical
structure
practicalstructure for
structurefor structure
individual
forindividual for individual
tailoring
individualtailoring of
tailoringof tailoring of
cardiovascular
ofcardiovascular cardiovascular
exercise exerc
exercise
cardiovascularexercise
intensity,
intensity, provides practical structure for individual tailoring of cardiovascular exercise
therapy
therapyin in
inpreventivetherapy
preventive
preventivehealth in preventive
health care
healthcare health
settings.
caresettings. care settings.
association:
settings. association: association:
Positive
association:Positive
Positive Positive
association;
association; association;
association: association:
No
association:NoNo N
therapy
therapy in preventive health
association; care settings.
: Improvement. association: Positive association;
association; association: No
association;
association;
association; : Improvement.
: Improvement.
association; :: Improvement.
Improvement.
5.2. F-I-T-T Principle: F(requency)
5.2.
5.2.
5.2. F-I-T-T
5.2.F-I-T-T
F-I-T-T Principle:
F-I-T-TPrinciple: F(requency)
Principle:F(requency)
Principle: F(requency)
F(requency)
Longitudinal shear stress is a major stimulus for adaptive endothelial responses
Longitudinal
Longitudinalshear
Longitudinal shear
shearstress
shear stress
stressis
stress isisaaaamajor
is major stimulus
majorstimulus
major stimulusfor for adaptive
foradaptive endothelial
adaptiveendothelial
endothelialresponses responses
responsesto to
to
Longitudinal exercise. Therefore, the totalstimulus
load of shear adaptive
stimulus rather endothelialthan the responses
peak itself to seems to
exercise.
exercise.
exercise. Therefore,
Therefore,
Therefore,
exercise. Therefore, the
the
the
the total total
total
total load
load
load of
load of shearof
of shear
shear
shear stimulus
stimulus
stimulus rather
rather
rather than
than
than the
thethe peak
peak
peak itself
itself
itself seems
seems
seems to
to be
be
to
the critical determinant [72].stimulus
An animal rather
study than the peak itself
demonstrated thatseems to be
high frequencies of r
the
be
the critical
thethecritical
critical
critical determinant
determinant
determinant
determinant [72].
[72]. An
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[72]. animal
animal
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study demonstrated
demonstrated
study demonstrated that
thathighhigh
high frequencies
frequencies
thatfrequencies
high frequencies of re-
ofre-
re-
peatedly [72]. elevated An shear study
stress demonstrated
induce adaptive that
mechanisms within theof endothelial ce
peatedly
ofpeatedly
repeatedly
peatedly elevated
elevated
elevated elevated shear
shear
[73].shearRepeated stress
shearstress
stress induce
induce
stress
induce
elevations adaptive
induce adaptive
adaptive
in adaptive
shear mechanisms
mechanisms
mechanisms
stress mechanisms within
within
within
could therefore the
within
the
explain endothelial
theendothelial
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As with aerobic exercise training, frequently repeated shorter bouts of exercise training
amight
considerable
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F-I-T-T Principle: I(ntensity)
5.3.
5.3. F-I-T-T
F-I-T-T
5.3.F-I-T-T Principle:
Principle:
F-I-T-TPrinciple:
Principle: I(ntensity)
There are only a few studies, that compared intensity-dependent vascular function
I(ntensity)
I(ntensity)
5.3. I(ntensity)
There are and
only structural effects of the same exercise modality.
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Thereare
There are onlyaaaafew
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areonly few
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vascular functional
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and
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effects
effects ofof
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exercise
exercise modality.
modality.
modality.
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training: One at
study mild, moderate,
conducted and
aa 12-week high exercise
aerobic, intensity
ergometer-based [74]. Interesting
Aerobic
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Aerobicexerciseexercise training:
training:
training: One
OneOne study
study
study conducted
conducted
conducted a a 12-week
12-week
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aerobic,
aerobic, ergometer-based
ergometer-based
ergometer-based
training interventiononly moderate
atatmild, but not high
moderate, and intensity
high led to improvements
exercise intensity of nitric oxide-dependent
[74]. [74].
Interestingly, only e
training
training intervention
trainingintervention
intervention
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atfunction
atintensity
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moderate,
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andandhigh
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high exercise
exercise
exercise
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intensity
The authors Interestingly,
[74].Interestingly,
[74].
concluded Interestingly,
that high intensities
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intensity improvements
led to improvements of nitric oxide-dependent
of nitric oxide-dependent endothelial en-
onlymoderate
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high intensity
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led
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massive acute that ofofnitric
nitricoxide-dependent
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en-
stress, pote
function
dothelial and less
function oxidative
and less stress.
oxidative The authors
stress. The concluded
authors concluded highthat intensities
high of aerobic
intensities of
dothelial function and less oxidative stress. The authors concluded that high intensities of
exercise might induce massive acute oxidative and inflammatory stress, potentially atten- short-ter
dothelial function tiallyand attenuating
less oxidative favorablestress. effects
The of
authors elevated shear
concluded stress.
that highConsistently,
intensities the
of
aerobic
aerobic exercise
exercise
exercisedecrease might
might induce
induce
in massive
massive acute
acute oxidative
oxidative and
and inflammatory
inflammatory stress,
stress, poten-
poten-
aerobic
uating favorable might
effectsinduce of vascular massive
elevated function
shear acute immediately
stress. oxidative
Consistently, after inflammatory
and anthe exercise
short-termbout becomes
stress,
decrease poten- larger
in with i
tially
tially attenuating
tiallyattenuating
attenuating favorable
creasingfavorable
favorable exercise effects
effects
effects of
intensities
of elevated
ofelevated
elevated
[75]. In shear
shear
contrast,
shear stress.
stress.
stress. very Consistently,
Consistently,
short bouts of
Consistently, the
thethe short-term
short-term or supr
near-maximal-
short-term
vascular function immediately after an exercise bout becomes larger with increasing exercise
decrease
decreasein
decrease in vascular
invascular
vascular function
maximal-intensity
function immediately
functionimmediatelyimmediately
exercise have after
after
after beenan
an exercise
anexercise
exercisebout
demonstrated bout becomes
boutbecomes
tobecomes
induce largerlarger
largerwith
similar with
withor
[76] in-
in-
in- even high
intensities [75]. In contrast, very short bouts of near-maximal- or supramaximal-intensity
creasing
creasing
creasing exercise
exercise
exercise intensities
intensities
intensities [75].
[75].
[75]. In In
In contrast,
contrast, very
very short
short bouts
bouts of
of near-maximal-
near-maximal- or
or supra-
supra-
exercise have been demonstrated to contrast,
induce similar very short [76] or bouts
evenofhigher near-maximal-
[77] vascular or supra-
effects
maximal-intensity
maximal-intensityexercise
maximal-intensity exercise
exercisehave have
havebeen been demonstrated
beendemonstrated
demonstratedto to
toinduce
inducesimilarsimilar
similar[76] [76]
[76]or or even
oreven
evenhigherhigher
higher
compared with traditional moderate-intensity aerobicinduce exercise. The underlying mecha-
Cells 2023, 12, 2544 8 of 15

nisms of this observation are not clear, but some evidence points towards an overexpression
of mitochondrial enzymes and, thus, an increased time to fatigue during exercise [78], a
stronger reduction in proinflammatory metabolites (i.e., oxidized low-density lipoprotein)
in the long term [79], and a higher expression of antioxidant enzymes (i.e., glutathione
peroxidase) [80]. Considering that the total load of shear stimulus rather than the peak itself
seems to be the critical determinant of endothelial adaptation to exercise [72], a prolonged
moderate-intensity workout might be preferred over a shorter high-intensity session to
improve vascular function. Having in mind the greater injury risk associated with high-
intensity training, more research is necessary to understand its potential beneficial effects
in vascular structure and function.
Resistance exercise training: For resistance training, little evidence exists about the
relationship between intensity and vascular adaptations, and it does not suggest a dose–
response relationship between resistance exercise intensity and improvements in vascular
function [71].

5.4. F-I-T-T Principle: T(ime)

Aerobic exercise training: The relationship of aerobic exercise with functional and
structural vascular adaptations has been described in a dose–response pattern, with higher
volumes of at least moderate-intensity exercise inducing higher functional vascular im-
provements [81]. However, the nature of this relationship is unclear, and no data exist
about a minimum necessary time of training or a ceiling effect. To date, no conclusion can
be drawn on the appropriate duration of a single session and, therefore, the appropriate
volume of elevated shear stress that would provide the optimal stimulus for endothelial
adaptation. One study found a higher increase in nitric oxide and a decrease in endothelial
microparticles in the plasma after 40 min of moderate-intensity aerobic exercise compared
to 20 min [82]. In contrast, one meta-analysis including aerobic exercise interventions longer
than 4 weeks of duration found no influence of session duration (20–60 min) on changes of
endothelial function independent of the overall training load [71]. Whether single training
sessions should have a longer or shorter duration to attain the best possible stimulus for
vascular adaptations cannot be answered now. However, as long as an adequate total
training volume is guaranteed, the balance between session length and frequency may be
chosen according to individual preferences of the trainee or general aspects of the training
plan, such as subsequent time required for recovery.
Resistance training: Very limited data exist on the relationship of resistance exercise
duration with functional and structural vascular adaptations. Therefore, no conclusions
can be drawn to date.

5.5. F-I-T-T Principle: T(ype)

Continuous versus interval aerobic exercise training: High-intensity interval training
(HIIT) is a frequently used method of improving fitness. A meta-analysis examining
the effects of HIIT relative to moderate-intensity continuous training (MICT) on vascular
function reported that HIIT was more effective at improving macrovascular (brachial
artery) function than MICT. However, the authors reported that the variability in secondary
outcome measures and the small sample sizes in the studies included limits this finding.
Nevertheless, that review suggested that four intervals of 4 min (4 × 4 HIIT) at 85–95% of
maximum or peak heart rate (HRmax/peak) interspersed with 3 min of active recovery
at 60–70% HRmax/peak three times per week for 12–16 weeks is a type of exercise to
enhance vascular function [83]. Another study [17] showed that a 4-week HIIT program
was superior to MICT for improving macrovascular function (as assessed by brachial artery
flow-mediated dilation) but not arterial stiffness (as assessed by pulse wave velocity). Over
12 months, changes in vascular function and arterial stiffness were similar for HIIT and
MICT. In accordance, a meta-analysis including studies with exercise training interventions
>4 weeks did not show any significant difference in the improvement of central arterial
stiffness between HIIT and MICT [84]. It should be mentioned, however, that the results of
Cells 2023, 12, 2544 9 of 15

studies comparing the two modes of aerobic exercise should be interpreted with caution,
as in many studies, the HIIT and MICT training was not performed with similar effort and
physiological strain. Controlling for the overall physiological stress exerted during the
training sessions is important when comparing the two exercise modes [85,86].
Aerobic, resistance (dynamic/isometric), and combined exercise training: Both aerobic
and resistance exercise seem to be associated with idiosyncratic patterns of blood flow
and shear stress, which lead to distinct effects on arterial function and remodeling [20].
One study found similar antegrade but different retrograde shear patterns in response to
aerobic and resistance exercise bouts [87], indicating different mechanisms of endothelial
stimulation. This observation may at least in part explain why both local and systemic
endothelial function show greater improvement after aerobic exercise compared to resis-
tance training [71]. In fact, repeatedly marked blood pressure elevations during resistance
training might reduce central arterial compliance [88,89]. As endothelial function was not
reduced in these studies, the clinical implications of this structural remodeling associated
with resistance training are unclear. However, it seems likely that they are independent of
an age-related decline in structural and functional vascular capacities. Although aerobic
exercise most likely is the stronger modifier of endothelial function, resistance training also
seems beneficial. For example, one recent study showed protective alterations of cerebral
blood flow after three months of resistance training [22].
Isometric exercise training has also been suggested as an effective intervention for
inducing favorable vascular adaptations. In detail, a recent cross-over study showed that
4 weeks of isometric training (wall squats) reduced arterial stiffness (as suggested by a
reduction in the augmentation index, derived from pulse-wave reflection) and total periph-
eral resistance [90]. In contrast, another study [91] found an improvement of microvascular
function (as assessed by peak blood flow during reactive hyperemia) with dynamic resis-
tance training (eight exercises, 50% of maximal repetition, three sets until moderate fatigue,
for 10 weeks, three times/week) and not isometric handgrip training (at 30% of maximum
voluntary contraction, four sets of 2 min). This later study did not find any additional
improvements of combined exercise training compared with dynamic resistance training in
vascular function. Differences between studies and exercise modes might be explained, at
least in part, by the different amount of muscle mass involved during the exercise sessions
and the type of blood vessels (micro- or macro-) examined.
All exercise modalities (aerobic, resistance, or combined) have been reported to in-
duce improvements in vascular function depending on the characteristics of the exercise
stimulus [71]. Because of distinct adaptations not only in the blood vessels but also in the
skeletal muscles and other body systems in response to both aerobic and resistance exercise,
training should involve both aerobic and resistance training modalities.

5.6. Individualization
Despite considerable scientific efforts, the mechanisms by which protective effects
of exercise contribute to the maintenance and improvement of vascular health are still
not fully understood. In consequence, evidence is lacking when it comes to the choice of
optimal training programs for the individual [20,92]. Furthermore, patients’ adherence
to exercise-based therapies is often undermined by the high efforts regular exercise re-
quires [93,94]. Individuals with the poorest functional capacity who carry the highest risk
of early frailty and disability, especially, do not seem reachable in many multifactorial
risk-based studies [95]. By providing some variations to F-I-T-T in a patient-centered,
flexible, and individual approach, training may be better tolerated, physically and mentally,
than traditional linear training methods. Therefore, methods like nonlinear periodized
exercise may promote patients’ adherence to exercise therapy while being equally effective
as high-intensity or moderate-intensity continuous training [6,7,96,97].
Furthermore, sex differences in the training adaptations of the vessels have been
reported [98,99]. Specifically, although in healthy, exercise-trained adults, large-elastic-
artery-stiffening progression was attenuated, and exercise interventions were shown to
Cells 2023, 12, 2544 10 of 15

improve arterial stiffness in sedentary middle-aged and older men and postmenopausal
women; regular aerobic exercise was reported to improve endothelial function in men (by
reducing oxidative stress and preserving NO bioavailability) but not to do so consistently
in estrogen-deficient postmenopausal women. Thus, potential sex differences should also
be taken into account when designing an exercise program.

6. Conclusions and Practical Implications

6.1. Conclusions
Exercise-induced hemodynamic changes lead to mechanical stress of the vascular
wall, the release of circulating growth factors from the endothelium, and the release of
exerkines from the exercising skeletal muscle and other organs. These three main adaptive
stimuli lead to an increased activity of several molecular pathways within the vascular
endothelial and smooth muscle cells, culminating in a better vasodilator and -constrictor
responsiveness, reduced arterial stiffness, arterio- and angiogenesis, higher antioxidative
capacities, and reduced oxidative stress. Recent research revealed a potential role of
enhanced mitochondrial biogenesis and mitophagy, substrate metabolism, and insulin
sensitivity in the vascular smooth muscle cells for exercise-induced vascular adaptations.
Acute bouts of exercise induce different vascular responses than regular training. Also,
vascular adaptability towards exercise is high at any age in both healthy individuals and
patients with cardiovascular diseases. This emphasizes the usefulness of exercise-based
vascular health prevention from children to centenarians. Although athletes’ arteries seem
to have higher functional capacities and less pathological structural remodeling than those
of nonathletes, clinical biomarkers often fail to demonstrate significant differences, at least
at a younger age. This puts the discussion on the table whether an already healthy vascular
organ can be improved by exercise to a superhealthy level or not.

6.2. Practical Implications

Current evidence about specific aspects of exercise training, such as F-I-T-T, is limited,
and exact training recommendations cannot be given. However, some practical implications
can be extracted:
• Some vascular adaptations, such as a favorable balance of angiogenesis and angiostasis
as well as of vasodilator and vasoconstrictor responsiveness, require regular exercise,
ideally throughout the entire life span. Therefore, individualization of exercise accord-
ing to objective and subjective factors should be sought to achieve the best possible
long-term training adherence.
• Repeated stimuli, at least every other day at initial stages and progressively increasing
to 5–7 days per week, might be necessary to use the full potential of favorable physio-
logical alterations, such as elevated blood pressure and improved glycemic control,
which last for about 24 h post exercise.
• The cumulative volume of elevated shear stress seems more important than peak
shear stress in terms of stimulating vascular remodeling. Thus, prolonged moderate-
intensity workouts may be favored over shorter sessions with very high intensities,
especially if injury prevention and long-term training adherence are important.
• High-intensity interval training may have additional benefits in the long-term, such
as increased antioxidative and metabolic capacities, and thus should also be part of
vascular exercise training.
• Resistance and aerobic exercise induce distinct macro- and microvascular adaptations;
thus, both types of exercise should be implemented in comprehensive training for
optimal vascular health.

Funding: This research received no external funding.

Acknowledgments: The collaboration between K.D. and K.K. developed within the VascAgeNet.
Conflicts of Interest: The authors declare no conflict of interest.
Cells 2023, 12, 2544 11 of 15

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