Physical activity and circulating endothelial progenitor cells: an intervention study

Physical activity and circulating endothelialprogenitor cells: an intervention studyFrancesca Cesari*, Francesco Sofi*,†,‡, Anna M. Gori*,‡, Ilaria Corsani†, Andrea Capalbo†, Roberto Caporale§,Rosanna Abbate*, Gian F. Gensini*,‡ and Alessandro Casini†

*Department of Medical and Surgical Critical Care, Thrombosis Centre, University of Florence, Florence, Italy,†Agency of Nutrition, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy, ‡Don Carlo Gnocchi Foundation,Florence, Italy, §Central Laboratory, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy

ABSTRACT

Background To assess the effect of a personalized physical activity programme on weight and circulating (CPC)and endothelial progenitor cells (EPC) in overweight and obese subjects.

Materials and methods Anthropometric measurements with body composition, cardiopulmonary test, maxi-mal stress exercise test with maximal oxygen uptake (VO2max) and a series of biochemical analyses were takenbefore (T0) and after 3 months of physical activity (T1) in a total of 80 overweight and obese subjects. CPC andEPC were determined using flow cytometry and were defined as CD34+, CD133+ and CD34+ ⁄ CD133+ for CPCand CD34+KDR+, CD133+KDR+ and CD34+CD133+KDR+ for EPC.

Results At the end of the programme, we divided the population into two groups, compliant individuals (groupA, n = 47) and noncompliant individuals (group B, n = 33). Group A reported significant reductions of weight by3Æ1% (P < 0Æ0001) and fat mass by 4Æ4% (P < 0Æ0001), while group B showed a percentage of increase in fatmass by 1Æ5% at T1. In group A, a trend of increase at T1 for circulating levels of CPC and EPC was observed,reaching the statistical significance for all the three types of EPC. On the contrary, group B showed no significantincrease in CPC and EPC. Furthermore, a significant correlation between decrease in fat mass and increase inCD133+ ⁄ KDR+ EPC was reported in group A (r = 0Æ50; P = 0Æ04).

Conclusion Three months of physical activity significantly improved anthropometric measurements. A benefi-cial effect of increased number of EPC in compliant individuals, in relation to weight loss, was observed.

Keywords Endothelial progenitor cells, obesity, physical activity, weight loss.

Eur J Clin Invest 2012

Introduction

Overweight, through an increased oxidative stress and

inflammation, has been demonstrated to determine a sub-

clinical atherosclerosis, representing a susceptibility factor

for the development of cardiovascular events [1]. To date,

the pathophysiological mechanisms linking obesity and

atherosclerosis are not well defined; recently, a role for

endothelial (EPC) and circulating progenitor cells (CPC)

has been reported. [2,3]. In 2008, Muller-Ehmsen et al. [4]

demonstrated for the first time that CPC are inversely

related to body weight, body mass index (BMI) and waist

circumference in a population of obese subjects, with a

higher prevalence of cardiovascular risk factors, such as

diabetes, hypercholesterolaemia and physical inactivity.

Moreover, it has also been reported that reduction of CPC

and, in particular, of the CD34+ subpopulation can be

reversible along with the reduction of the caloric intake

through a dietary intervention [4].

Recently, a study conducted in a limited sample of obese sub-

jects examined the effect of a dietary intervention on early out-

growth EPC number and functional properties, by

demonstrating that, after a 6 months of intervention, a signifi-

cant weight reduction was able to restore the functional capac-

ity of EPC [5].

Actually, physical exercise is an important part of obesity

treatment concepts, by inducing and supporting fat mobiliza-

tion from adipose tissue [6]. Over the past few years, research

about the effect of physical activity on stem cells’ mobilization

produced some interesting findings. In fact, physical exercise

has been reported to augment the number of both CPC and

EPC in coronary artery disease patients as well as in athletes,

European Journal of Clinical Investigation 1

DOI: 10.1111/j.1365-2362.2012.02670.x

ORIGINAL ARTICLE

showing a positive effect on stem cells’ mobilization [7–10]. To

date, however, the effect of weight loss obtained through a

personalized physical activity programme able to induce

adipose tissue lipolysis, and not limited a restrictive diet, on

CPC and EPC number has not been investigated.

We aimed this study to assess, in a population of overweight

and obese subjects, the effect of a personalized physical activity

programme on CPC and EPC number and on weight reduction.

Materials and methods

Study populationEighty [40 M, 40 F; median age, 44Æ5 years (range, 24–69)] over-

weight and obese subjects referring to the Agency of Nutrition

of the University Hospital of Careggi, Florence for a weight loss

programme were recruited through questionnaires, advertise-

ments in the local newspaper, primary care, and the home ser-

vice administration organized by the local authorities.

Eligibility criteria were BMI > 25 kg ⁄ m2, with the absence of

any other established cardiovascular risk factors (i.e. hyperten-

sion, diabetes, dyslipidaemia, family history of cardiovascular

diseases), 18–70 years of age and stable weight (modification

not > 2 kg during the last 12 months). Exclusion criteria were

presence of diagnosed type I and II diabetes, blood hyperten-

sion, dyslipidaemia, inability to undertake a maximal exercise

test to achieve maximum aerobic capacity, people with medica-

tions known to affect heart rate or body composition, recent

cardiac problems requiring hospital care, recent hip fracture or

surgery during the last 6 months, present cancer treatment,

stroke within the last 2 years, pregnancy or lactation. The local

Ethic Committee approved the study, and all participants gave

written informed consent. The study conforms to the STROBE

statement along with reference to STROBE statement and to the

broader EQUATOR guidelines [11].

Study designAt the beginning and at the end of the study, full medical evalu-

ation consisting of physical examination, blood tests, anthropo-

metric measurements, resting electrocardiogram, resting

energy expenditure, maximal exercise test and maximal oxygen

uptake was obtained from all the participants. BMI was calcu-

lated as weight (kg) ⁄ height (m2). Bioelectrical impedance for

the measurement of body composition was performed with the

use of a soft tissue analysis ⁄ bioelectrical impedance analysis

device (Tanita B420MA; SensorMedics Italia Srl, Milan, Italy).

Cardiorespiratory fitness testAll participants underwent at baseline and at the end of the

intervention a graded bicycle test with spirometry until exhaus-

tion. Subjects started exercising at a load of 25 Watts, with an

incremental load of 5 Watts every 2 min. Twelve-lead ECG and

heart rate were recorded continuously, and automatic cuff

blood pressure was measured every 2 min and at peak exercise.

The exercise test was started when oxygen consumption (VO2)

at rest showed stable levels. The recovery period lasted 4 min

or until the heart rate and blood pressure normalized, which-

ever was longer. Subjects were encouraged to exercise until

exhaustion, and all of them performed a maximal test according

to the identification of individual anaerobic threshold (IAT).

The IAT indicates the exercise intensity corresponding to the

maximal lactate steady state. This corresponds to the individual

level of physical activity for training.

Exercise respiratory variables were continuously recorded

breath-by-breath by portable lightweight equipment, which did

not interfere with movements (K4b; Cosmed, Rome, Italy). Full

calibration of the system was obtained before each test. During

the test, subjects were wearing a neoprene mask holding a sup-

port for the gas sampling line and pneumotachograph. Five

commonly used markers of maximal and threshold cardiorespi-

ratory capacity were provided in the main test: resting heart

rate, maximal oxygen uptake (VO2max), IAT and maximal heart

rate. IAT was estimated by spirometer algorithms.

Physical activity programmeParticipants were instructed to attend a programme of physical

activity, which consisted of 45-min session of aerobic exercise

(walking briskly or moderate running) to be performed three

times per week, with a strict control of the heart rate in order

not to exceed their individual IAT. All subjects were encour-

aged to purchase a heart rate transmitter belt, together with a

receiver watch. A tailored physical activity programme was

determined for each participant, with indications on heart rate

to be followed for the entire session of physical activity.

Furthermore, to avoid confounding factors for weight

modifications, the subjects were recommended not to modify

the quantity and quality of their usual diet. At the end of the

3-month intervention programme with physical activity, the

study population was divided into compliant individuals

(group A) and noncompliant individuals (group B). Compliant

individuals were identified as subjects who either self-reported

an adherence to the whole training programme or showed an

increase in VO2max > 10% (median level of increase among the

subjects who reported to have adhered to the programme) after

3 months of intervention.

Laboratory parametersBlood sample was taken in the morning after an overnight fast-

ing and was collected from the antecubital vein into evacuated

plastic tubes (BD Vacutainer; Becton Dickinson, Plymouth, UK)

containing ethylenediaminotetracetate 0Æ17 M for CPC and EPC

evaluation. Whole venous blood was also collected in tubes

without anticoagulant. Haematological parameters, lipid

2 ª 2012 The Authors. European Journal of Clinical Investigation ª 2012 Stichting European Society for Clinical Investigation Journal Foundation

F. CESARI ET AL. www.ejci-online.com

profile and blood glucose were analysed using conventional

procedures. CPC and EPC number was assessed contemporar-

ily using flow cytometry as previously described [12]. CPC

were defined as cells forming a cluster with low side scatter

and low-to-intermediate CD45 staining and positive for CD34,

CD133 and CD34 ⁄ CD133. EPC were identified through the

expression of CD34, KDR and CD133 and were considered as

CD34+ ⁄ KDR+, CD133+ ⁄ KDR+ and CD34+ ⁄ CD133+ ⁄ KDR+.

Statistical analysisStatistical analysis was performed by the SPSS (Statistical

Package for Social Sciences Inc., Chicago, IL, USA) software for

Windows (Version 14.0). Results are expressed either as

mean ± standard deviation (SD) or as median and range, as

appropriate. Sample size was calculated as a number of subjects

able to detect a difference after the physical activity programme,

in line with the modest effect of physical activity observed in

previous studies (approximately 7% of the initial weight). The

analyses were simplified by calculating the absolute change for

each variable tested (mean value at baseline subtracted from the

mean value after intervention for each subject) with indepen-

dent t sample tests. Data that were not normally distributed

were logarithmically transformed or analysed by the nonpara-

metric Wilcoxon signed-ranked test. Data were analysed using

paired t tests for significant differences between changes

observed during test and control intervention periods. A gen-

eral linear model for repeated measurements (interaction term:

before and after intervention) adjusted for age, gender and

change of VO2max was performed to test whether weight change

followed by physical activity intervention programme was able

to determine significant changes of CPC and EPC. A P-value

< 0Æ05 was considered to indicate statistical significance.

Results

All the enrolled subjects completed the study and entered into

the final analysis. Mean BMI of the study population was

31Æ5 ± 5Æ6 kg ⁄ m2.

Demographic and clinical characteristics of the two groups at

baseline were reported in Table 1. No significant differences

between the group A and group B were detected. In Table 2,

changes after the intervention programme for anthropometric

and biochemical variables in both groups are reported. At the

end of the programme, group A subjects showed a significant

decrease in anthropometric measurements such as BMI

()3Æ1%), total weight ()3Æ1%) and fat mass ()4%), with a signifi-

cant improvement of free-fat mass (+0Æ9%) and cardiopulmo-

nary capacity, as detected by VO2max (+10Æ8%). No significant

changes were reported for biochemical parameters. On the

contrary, group B subjects showed no significant improvement

in anthropometric measurements with an increase in fat mass

(+1Æ5%) and a decrease in cardiopulmonary capacity, as seen by

VO2max ()6Æ3%).

In a subgroup of subjects (n = 40; 22 M, 18 F with a median

age of 48 years), similar for characteristics with the whole study

population, we analysed CPC and EPC at baseline and at the

end of the programme to test the possible influence of such per-

sonalized intervention programme on CPC and EPC. Of these,

21 were ascribed to group A and 19 to group B. At baseline, no

significant differences for all the population of CPC and EPC

between group A and group B were observed (data not

reported). To test the effect of the personalized programme

with physical activity on the number of CPC and EPC, we per-

formed a general linear model for repeated measurements after

adjustment for age, gender and changes of VO2max (Table 3).

Three months of personalized programme with physical activ-

ity were able to determine a significant increase in all the three

groups of EPC (CD34+ ⁄ KDR+: +33Æ3%; CD133 ⁄ KDR+: +35%;

CD34+ ⁄ CD133+ ⁄ KDR+: +35Æ7%) in group A, while no signifi-

cant changes in group B were detected. Moreover, to investi-

gate the possible association between changes of

anthropometric measurements at the end of the programme

and changes of CPC and EPC, we performed correlation analy-

ses, which revealed a significant correlation between decrease

in fat mass and increase in CD133+ ⁄ KDR+ EPC (R = 0Æ50,

P = 0Æ04) in group A, whereas no significant correlations in

group B were reported.

Discussion

In this intervention study, we demonstrated the beneficial

effects of a personalized physical activity programme on EPC

number as well as on weight reduction and body composition

Table 1 Demographic and clinical characteristics of the studypopulation at baseline

Group A

(n = 47)

Group B

(n = 33) P value

Age, years* 46 (24–69) 41 (25–67) 0Æ2

Males, n (%) 23 (48Æ9) 17 (51Æ5) 0Æ2

Smoking habit 7 (14Æ9) 5 (15Æ1) 0Æ2

BMI, kg ⁄ m2† 32Æ3 ± 5Æ2 31Æ5 ± 4Æ9 0Æ9

Total weight, kg† 92Æ3 ± 17Æ1 91Æ5 ± 18Æ1 0Æ4

Fat mass, %† 34Æ6 ± 7Æ6 32Æ2 ± 10Æ3 0Æ4

Fat mass, kg† 32Æ2 ± 9Æ9 29Æ6 ± 12Æ7 0Æ3

VO2max, mL ⁄ kg ⁄ min† 2Æ04 ± 0Æ53 2Æ22 ± 0Æ73 0Æ5

BMI, body mass index.

*Median and range.†Mean ± SD.


ENDOTHELIAL PROGENITOR CELLS AND EXERCISE

of obese and overweight subjects. Indeed, a 3-month interven-

tion programme with physical activity was able to decrease

total weight and percentage of fat mass, by augmenting the

number of circulating EPC. Moreover, a significant correlation

between the decrease of percentage of fat mass and the increase

of EPC, suggesting a possible link between adipose tissue

reduction and EPC mobilization, has been also reported.

Over the last few years, a beneficial role for bone-marrow-

derived EPC and CPC in the vascular homeostasis has emerged

[13]. EPC have been demonstrated to be key player in restora-

tion of injured endothelium, either by integrating in the endo-

thelial cell layer or by secreting angiogenic growth factors [13].

Currently, several factors have been reported to influence the

number of circulating EPC: decreased levels have been found to

be associated with increasing age, hypertension, smoking habit,

hypercholesterolaemia and BMI, while increased levels have

been reported to be associated with the use of some pharmaco-

logical treatments such as statins, erythropoietin, peroxisome

Table 2 Changes of anthropometric and biochemical variables after intervention with physical activity

Group A Group B

T0 T1 P (T1 ) T0) T0 T1 P (T1 ) T0)

BMI, kg ⁄ m2 32Æ3 ± 5Æ2 31Æ3 ± 4Æ9 < 0Æ0001 31Æ5 ± 4Æ9 31Æ5 ± 4Æ9 0Æ8

Total weight, kg 92Æ3 ± 17Æ1 89Æ4 ± 15Æ9 < 0Æ0001 91Æ5 ± 18Æ1 91Æ5 ± 18 0Æ8

Fat mass, kg 32Æ2 ± 9Æ9 30Æ9 ± 9Æ5 < 0Æ0001 29Æ6 ± 12Æ7 30 ± 12Æ6 0Æ3

Fat mass, % 34Æ6 ± 7Æ6 33Æ3 ± 7Æ6 < 0Æ0001 32Æ2 ± 10Æ8 32Æ7 ± 10Æ8 0Æ005

Free-fat mass, kg 56Æ2 ± 13Æ1 56Æ7 ± 13Æ2 < 0Æ0001 60Æ2 ± 13Æ9 59Æ8 ± 13Æ2 0Æ08

VO2max, mL ⁄ kg ⁄ min 2Æ04 ± 0Æ53 2Æ26 ± 0Æ56 < 0Æ0001 2Æ22 ± 0Æ73 2Æ08 ± 0Æ69 < 0Æ0001

WBC, cells ⁄ lL* 6560 (5930–8400) 6850 (6700–8140) 0Æ6 7000 (4330–9180) 5590 (4600–7680) 0Æ2

Blood glucose, g ⁄ L 0Æ95 ± 0Æ12 0Æ89 ± 0Æ07 0Æ5 0Æ98 ± 0Æ09 0Æ95 ± 0Æ07 0Æ2

Total cholesterol, mg ⁄ dL 200Æ4 ± 55Æ8 196 ± 26Æ2 0Æ3 194Æ1 ± 33Æ9 198Æ3 ± 39Æ1 0Æ6

LDL-cholesterol, mg ⁄ dL 129Æ2 ± 43Æ6 124Æ6 ± 19 0Æ6 121Æ5 ± 32Æ7 123Æ1 ± 37Æ1 0Æ4

HDL-cholesterol, mg ⁄ dL 53Æ2 ± 10Æ1 55Æ3 ± 10Æ2 0Æ1 52Æ9 ± 11 53Æ8 ± 10Æ6 0Æ5

Triglycerides, mg ⁄ dL 90Æ9 ± 22Æ2 80Æ7 ± 10Æ1 0Æ6 92Æ2 ± 32Æ2 96Æ4 ± 51Æ2 0Æ6

BMI, body mass index; WBC, white blood cells.

Values are expressed as mean ± SD.

*Median and range.

Bold values = P < 0.05.

Table 3 Changes of circulating (CPC) and endothelial progenitor cells (EPC) after intervention with physical activity

Group A (n = 21) Group B (n = 19)

T0 T1

Change

(T1 ) T0) P T0 T1

Change

(T1 ) T0) P

CPC

CD34+, cell ⁄ 106 events 336 (259–414) 420 (346–493) 84 ()9; 175) 0Æ07 369 (250–488) 396 (267–526) 27 ()89; 33) 0Æ3

CD133+, cell ⁄ 106 events 321 (246–396) 384 (314–456) 63 ()39; 167) 0Æ2 364 (247–481) 389 (253–526) 25 ()40; 92) 0Æ4

CD34 ⁄ 133+, cell ⁄ 106 events 294 (224–364) 358 (274–442) 64 ()64; 191) 0Æ3 344 (227–461) 363 (215–511) 19 ()78; 117) 0Æ6

EPC

CD34+ ⁄ KDR, cell ⁄ 106 events 14 (9–19) 21 (15–27) 7 (0; 14) 0Æ04 18 (12–23) 21 (13–28) 3 ()3; 9) 0Æ3

CD133+ ⁄ KDR, cell ⁄ 106 events 13 (8–18) 20 (15–24) 7 (1; 13) 0Æ02 18 (12–24) 21 (14–28) 3 ()2; 9) 0Æ2

CD34+ ⁄ 133 ⁄ KDR, cell ⁄ 106 events 9 (6; 13) 14 (11; 17) 5 ()1; 9) 0Æ04 15 (11–18) 18 (12–24) 3 ()2; 9) 0Æ2

Values are expressed as geometric mean and 95% CI; General linear model adjusted for age, gender and change of VO2max.

Bold values = P < 0.05.



proliferator-activated receptor gamma-agonists and angiotensin

II receptor antagonists [4,14,15].

In our study, we demonstrate, for the first time, that a ‘lipo-

lytic’ physical exercise, that is below the anaerobic individual

threshold, is able to determine not only a significant weight

reduction, but also an increase of EPC as well as a modification

of the composition of the body mass, with a significant decrease

in fat mass and increase in free-fat mass.

Owing to the nature of the study, we are not able to distin-

guish which of the two main components – physical exercise

and weight change – is the main contributor of the increased

levels of EPC. To determine which of the two components,

physical exercise by itself or weight reduction, determined by

physical exercise, is mostly related to the increase of EPC, an ad

hoc study should be performed.

Actually, several studies reported the positive influence of

physical exercise on EPC and CPC levels and function in both

patients with vascular disease and healthy subjects, by sug-

gesting this effect on progenitor cells to be one of the most

important beneficial outcomes of physical exercise, probably

mediated by a shear stress-induced up-regulation of endothe-

lial nitric oxide synthase [7–9,14]. Moreover, two recent stud-

ies conducted among obese subjects reported that a period of

dietary caloric restriction with a subsequent weight loss is able

to increase the number of CPC and determine a beneficial effect

on the functional properties of early outgrowth EPC [4,5].

In our sample of subjects, we showed a significant and

inverse relationship between fat mass’ loss and EPC. The link

between adipose tissue and EPC is, to date, only speculative. In

2007, Matsuo et al. [16] demonstrated in coronary artery disease

patients plasma levels of adiponectin significantly associated

with an increase of EPC number. In addition, the effects of

adiponectin on EPC have been recently investigated in animal

models of hindlimb ischaemia, demonstrating that it regulates

the level of circulating EPC in response to ischaemic injury,

possibly stimulating, in cultured progenitor cell populations,

the expression of endothelial cell marker proteins, the incorpo-

ration in an endothelial network, as well as the promotion of

EPC differentiation and function [17].

However, in the present study, we chose not to use dietary

approaches for weight reduction in overweight and obese sub-

jects, as the primary aim of the study was to investigate the

effects of physical activity ‘per se’ on moderate reduction of

weight and progenitor cells and not to test the effect of a spe-

cific dietary plan.

Therefore, we could hypothesize that the ‘prescription’ of the

physical activity able to achieve a significant weight loss, and in

turn a significant increase of EPC, can vary, so requiring a per-

sonalized approach. In fact, only among subjects who resulted

to follow the personalized prescription, despite starting from

lower EPC levels, the compliance to the programme was able to

exceed the unfavourable effect of older age and greater BMI.

Moreover, in this group of patients, a decrease in fat mass and

an increase in EPC have been evidenced, suggesting perhaps an

effect of a moderate reduction of weight and adipose tissue on

EPC mobilization, rather than of physical exercise.

Some limitations are present in this study. First of all, the lim-

ited number of subjects investigated as well as the limited dura-

tion of follow-up allows us only to hypothesize the possible

relation between physical exercise and increase of CPC and

EPC, and secondly, the use of an arbitrary method to identify

subjects ‘compliant individuals’. The compliance to such inter-

vention studies is not easy to measure and establish. We used

the combination of a self-reported statement of adherence and,

as an indirect method to measure the adherence, the increased

level of VO2max at the end of the training programme. However,

we are fully aware that this is not a specific method to establish

the real compliance of the subjects and that this could have led

to an underestimation or overestimation of number of subjects

in the two groups. Nonetheless, strengths of the present study

are the type of intervention, as well as the subjects studied.

Indeed, the intervention was based only on physical activity,

and not on dietary modification, it was personalized according

to subject’s variables, and the study population represented a

typical ‘primary prevention’ group where no other risk factor

or comorbidity was present.

In conclusion, the present intervention study confirms the

positive effect of physical activity on weight reduction and vas-

cular health, as shown by a significant increase of EPC. Further

studies investigating type, duration and intensity of physical

activity to be conducted for obtaining a persistent increase in

such progenitor cells need to be conducted.

Address

Department of Medical and Surgical Critical Care, Thrombosis

Centre, University of Florence, Largo Brambilla, 350134

Florence, Italy (F. Cesari, F. Sofi, A. M. Gori, R. Abbate,

G. F. Gensini); Agency of Nutrition, Azienda Ospedaliero-

Universitaria Careggi, Largo Brambilla, 350134 Florence, Italy

(F. Sofi, I. Corsani, A. Capalbo, A. Casini); Don Carlo Gnocchi

Foundation, Onlus IRCCS, Impruneta, Largo Brambilla, 350134

Florence, Italy (F. Sofi, A. M. Gori, G. F. Gensini); Central

Laboratory, Azienda Ospedaliero-Universitaria Careggi,

Largo Brambilla, 350134 Florence, Italy (R. Caporale).

Correspondence to: Francesco Sofi, MD, Department of

Medical and Surgical Critical Care, Thrombosis Centre,

Viale Morgagni, 85, 50134 Florence, Italy.

Tel.: +39-055-7949420; fax: +39-055-7949418;

e-mail: [email protected]

Received 2 September 2011; accepted 3 March 2012


ENDOTHELIAL PROGENITOR CELLS AND EXERCISE

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Physical activity and circulating endothelial progenitor cells: an intervention study