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. Author manuscript; available in PMC: 2015 Jul 1.
Published in final edited form as: Eur J Appl Physiol. 2014 Mar 19;114(7):1377–1384. doi: 10.1007/s00421-014-2861-6

Circulating angiogenic and inflammatory cytokine responses to acute aerobic exercise in trained and sedentary young men

Rian Q Landers-Ramos 1, Nathan T Jenkins 1, Espen E Spangenburg 1, James M Hagberg 1, Steven J Prior 2
PMCID: PMC4048778  NIHMSID: NIHMS577136  PMID: 24643426

Abstract

Purpose

Endurance exercise training can ameliorate many cardiovascular and metabolic disorders and attenuate responses to inflammatory stimuli. The purpose of this study was to determine whether the angiogenic and pro-inflammatory cytokine response to acute endurance exercise differs between endurance-trained and sedentary young men.

Methods

Ten endurance-trained and 10 sedentary healthy young men performed 30 minutes of treadmill running at 75% VO2max with blood sampling before and after exercise. Plasma concentrations of tumor necrosis factor (TNF)-alpha, interleukin (IL)-8, IL-6, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), placental growth factor (PlGF), and soluble VEGF receptor-1 (sFlt-1) were measured by multiplex ELISA.

Results

Acute exercise increased IL-6 by 165% (P < 0.05), IL-8 by 32% (P < 0.05), PlGF by ~16% (P < 0.05), sFlt-1 by 36% (P < 0.001), and tended to increase bFGF by ~25% (P = 0.06) in main effects analyses. TNF-α and VEGF did not change significantly with exercise in either group. Contrary to our hypothesis, there were no significant differences in TNF-α, IL-6, VEGF, bFGF, PlGF, or sFlt-1 between groups before or after acute exercise; however, there was a tendancy for IL-8 concentrations to be higher in endurance-trained subjects compared to sedentary subjects (P = 0.06).

Conclusions

These results indicate that 30 minutes of treadmill running at 75% VO2max produces a systemic angiogenic and inflammatory reaction, but endurance exercise training does not appear to significantly alter these responses in healthy young men.

Keywords: Exercise training, inflammation, growth factors, interleukin, endurance exercise

Introduction

Regular endurance exercise is an established method for the prevention and treatment of many cardiovascular (CV) and metabolic disorders. A single bout of endurance exercise triggers the release of angiogenic and inflammatory cytokines(Kraus 2004; Nielsen and Pedersen 2007; Nieman et al. 2012). Conversely, endurance exercise training may be protective against CV diseases, in part, through production of exercise-induced signals for vascular- and muscle metabolism-related adaptations (Hoier et al. 2013; Jensen 2004; Nielsen and Pedersen 2007; Nieman et al. 2012; Ostrowski et al. 1998) and attenuation of chronic exposure to an active inflammatory process often seen in disease states (Ambarish et al. 2012; Gokhale et al. 2007; Trøseid 2004; Wellen and Hotamisligil 2005).

Cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-8 play roles in both pathological signaling and physiological adaptations to exercise. For instance, elevated plasma concentrations of TNF-α are observed in disease states (Popa et al. 2007) and in response to prolonged or high-intensity acute exercise (Nieman et al. 2012; Ostrowski et al. 1998). High plasma IL-6 levels are associated with inflammation and metabolic disorders (Wellen and Hotamisligil 2005), but IL-6 concentrations also increase exponentially in response to increased exercise intensity or duration (Nieman et al. 2012; Ostrowski et al. 1998; Ronsen et al. 2002). IL- 8 can promote angiogenesis in microvascular endothelial cells (Heidemann 2002), and may contribute to exercise-induced increases in skeletal muscle capillarization (Heidemann 2002; Nielsen and Pedersen 2007; Nieman et al. 2012).

Acute endurance exercise has been found to stimulate vascular endothelial growth factor (VEGF) production which contributes to growth and maintenance of the vasculature (Lieb et al. 2009), increases in capillary density, and mobilization of circulating angiogenic cells (Kraus 2004; Mobius-Winkler et al. 2009). Basic fibroblast growth factor (bFGF) is another potent angiogenic protein (Gu et al. 1997), but the effects of exercise on bFGF concentrations are not well understood (Wahl et al. 2010). Placental growth factor (PlGF) has diverse roles in inflammation and ischemia-induced angiogenesis (Dewerchin and Carmeliet 2012; Luttun et al. 2002) and is expressed in a number of cell types in response to hypoxia or inflammatory cytokines such as TNF-α (Dewerchin and Carmeliet 2012). Soluble fms-like tyrosine kinase-1 (sFlt-1) acts as an endogenous inhibitor of VEGF and PlGF to help maintain concentrations within normal physiological levels. Clinical studies suggest that elevated sFlt-1 is associated with a reduced risk of CV disease and endurance exercise may promote this protective response (Bailey et al. 2006; Blann et al. 2002; Lieb et al. 2009).

Regular endurance exercise training is suggested to attenuate the inflammatory response to exercise. Altered responses in IL-6, TNF-α, and VEGF have been found in response to endurance exercise training (Croft et al. 2009; Fischer 2004; Gokhale et al. 2007; Kraus 2004) while others have found no differences between sedentary and endurance-trained resting or post-exercise plasma VEGF concentrations (Kraus 2004). Thus, it is still unclear whether exercise training can alter the angiogenic or inflammatory response to an acute bout of exercise. It is possible that differences among these studies are attributable to differences in exercise protocols with respect to the duration of exercise (50 min-3 hrs), the intensity of exercise, and the timing of blood sampling.

Despite differences in experimental protocols among studies, there is evidence that young, endurance trained athletes have an attenuated inflammatory response to an acute exercise bout (Croft et al. 2009; Fischer 2004; Gokhale et al. 2007). Thus, the purpose of this study was to determine whether acute exercise-induced changes in circulating concentrations of angiogenic and pro-inflammatory cytokines would differ between endurance-trained and sedentary young men when tested using a standardized bout of endurance exercise. In the current study, the exercise protocol was standardized according to American College of Sports Medicine (ACSM) guidelines [30min/day of vigorous aerobic exercise on most days/week (Medicine 2012)] to reflect an exercise stimulus that is recommended for most young adults. We hypothesized that basal cytokine concentrations would be lower in the endurance-trained subjects compared to sedentary and that an acute bout of treadmill running would increase the angiogenic response while producing a lower inflammatory response in endurance-trained subjects compared to their sedentary counterparts.

Methods

Screening

Twenty men 18–35 years of age participated in the study and the screening criteria for this study have been described previously (Jenkins et al. 2011). Briefly, all participants were nonsmokers with no history of CV disease or diabetes. Subjects were normotensive and were not on cholesterol, antihypertensive, or antihyperglycemic agents. Endurance-trained individuals (n = 10) performed at least 4 hrs/wk of vigorous endurance exercise, and sedentary individuals (n = 10) reported engaging in exercise for < 20 min/d on < 2 days/wk. Subjects were matched for age (± 1) and body mass index (± 0.6). Sufficient plasma samples were available from 8 endurance-trained and 9 sedentary subjects and are included in this report. This study was approved by the University of Maryland College Park Institutional Review Board, and all participants provided written informed consent.

Maximal graded exercise test and body composition

All testing occurred in the morning after an overnight fast. Participants refrained from alcohol, vitamins, and caffeine for 12 hrs and antihistamines or non-steroidal anti-inflammatory drugs (NSAIDs) for 24 hrs prior to testing. Maximal oxygen uptake (VO2 max) was assessed using a constant-speed treadmill protocol with a 2% increase in incline every 2 min until exhaustion. The treadmill speed was chosen by the investigator based on each subject’s experience, typical running speed, and heart rate such that VO2max was achieved in 6–12 min. Pulmonary ventilation and expired gas concentrations were analyzed in real time using an automated computerized indirect calorimetry system (Oxycon Pro, Viasys). VO2 was considered maximum if a plateau was achieved (increase in VO2 of < 250 ml/min with increased work). In the absence of a clear plateau, tests were verified to meet at least two of the following secondary criteria of maximal effort: a respiratory exchange ratio >1.10, a rating of perceived exertion >18, and a peak heart rate within 10 beats/min of the age-predicted maximum. Heart rate was measured during the test using heart rate monitors (Polar Electro Inc, Lake Success, NY). Body composition was estimated using the 7-site skinfold procedure (Jackson and Pollock 2004).

Submaximal exercise test

Subjects reported to the laboratory 2–7 days following their VO2max test. Participants refrained from food, alcohol, vitamins, and caffeine for 12 hrs and antihistamines or NSAIDs for 24 hrs prior to testing. The endurance-trained subjects performed one of their usual exercise training sessions 16–24 hrs before this test and the sedentary subjects remained inactive during this time. Seated blood pressure was measured and blood samples were obtained in EDTA tubes before and 30 minutes after completion of exercise for assessment of conventional CV risk factors (baseline sample only), hematocrit, hemoglobin (Dill and Costill 1974) and changes in plasma volume. Blood was centrifuged and plasma was frozen in aliquots at −80°C until analyses were performed. The submaximal exercise test consisted of 30 min of treadmill running at 75% of the subject's VO2 max. The treadmill speed was the same as that used for the maximal test and % incline was adjusted to elicit the appropriate intensity according to the ACSM equation for VO2 during treadmill running (Medicine 2009). Intensity was verified using the heart rate reserve method. Briefly, heart rate reserve was calculated by subtracting subject’s resting heart rate from their maximal heart rate. Heart rate reserve was multiplied by 75% and added to the resting heart rate to determine the heart rate at which subjects performed their submaximal exercise.

Measurement of plasma cytokines

Plasma concentrations of IL-6, IL-8, TNF-α, VEGF, bFGF, PlGF, and sFlt-1 were measured in duplicate by multiplex ultra-sensitive sandwich immunoassays (Meso Scale Discovery, Gaithersburg, MD) according to the manufacturer’s instructions. Briefly, the plasma sample (or manufacturer-provided standards) and a detection antibody solution are added in sequential steps to 96-well plates pre-coated with capture antibodies in spatially distinct spots. A buffer is then applied to provide an appropriate electrochemiluminescent signal and the plate is read on a Meso Scale Discover SECTOR Imager 2400. The average intra-assay coefficients of variation were 4–8% in these assays. All samples were assayed on the same plate to avoid inter-assay variability.

Statistics

Data are reported as means ± SEM. Subject characteristics were analyzed using unpaired t-tests. Cytokine data were analyzed using a two-factor [group (endurance-trained or sedentary) × time (baseline and after exercise)] repeated-measures ANOVA. Assumptions of normality and homoscedasticity were verified for all data using SPSS version 19 (IBM, Armonk, NY) at a P > 0.05. The criterion for statistical significance was P ≤ 0.05.

Results

Subject characteristics

Characteristics of the subjects in this study can be found in Table 1. The basic characteristics of this subject population have been published previously (Jenkins et al. 2011). Briefly, there were significant differences in fitness between sedentary and endurance-trained subjects with trained subjects having 33% higher VO2max than the sedentary subjects (P < 0.05). Despite matching for BMI, percent body fat was significantly higher in sedentary subjects (P < 0.05). Circulating lipid concentrations were also slightly but significantly different between groups with sedentary subjects having higher triglycerides and VLDL cholesterol compared to endurance trained subjects (both P < 0.05).

Table 1.

Subject Characteristics

Endurance-Trained Sedentary
(n = 8) (n = 9)
Age (y) 25 ± 1 25 ± 2
BMI (kg·m−2) 22.1 ± 0.7 23.5 ± 0.8
Body Fat (%) 6.9 ± 0.5 14.5 ± 1*
Glucose (mg·dl−1) 77 ± 2 80 ± 4
Cholesterol (mg·dl−1) 167 ± 6 166 ± 12
HDL-C (mg·dl−1) 66 ± 4 56 ± 4
LDL-C (mg·dl−1) 89 ± 5 92 ± 12
TC/HDL 2.6 ± 0.1 3.1 ± 0.3
LDL/HDL 1.4 ± 0.1 1.7 ± 0.3
VLDL-C (mg·dl−1) 11 ± 1 18 ± 2*
Triglycerides (mg·dl−1) 58 ± 5 92 ± 9*
SBP (mm Hg) 121 ± 3 119 ± 2
DBP (mm Hg) 73 ± 2 76 ± 3
MAP (mm Hg) 89 ± 2 90 ± 3
VO2max
  l·min−1 4.8 ± 0.1 3.6 ± 0.1*
  ml·kg·min−1 70.2 ± 1 47.1 ± 1.7*
  ml·kg FFM·min−1 75.5 ± 1 55.1 ± 2*
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*

Statistically significant difference between groups (P<0.05).

Circulating cytokine response to exercise

Responses of circulating VEGF, bFGF, PlGF, and sFlt-1 concentrations to acute exercise are shown in Figure 1. There were no significant interactions for VEGF, bFGF, PlGf or sFlt-1 (P < 0.05). VEGF concentrations were not different after acute exercise (Figure 1A). However, there was a main effect of acute exercise (i.e., time) on PlGF concentrations (16.2 ± 0.7 vs. 18.7 ± 1.3 pg/mL; Figure 1B; P < 0.05). A main effect of acute exercise was also seen on sFlt-1 concentrations (166 ± 7 vs. 225.6 ± 11.5 pg/mL; Figure 1C; P < 0.001), and a there was a tendency for elevated bFGF concentration following acute exercise (6.2 ± 0.6 vs. 7.8 ± 0.9 pg/mL; Figure 1D; P = 0.06). There were no statistically significant differences between groups (i.e. no group main effect) in VEGF, bFGF, PlGF, or sFlt- 1 at baseline, nor after acute exercise (Figure 1).

Figure 1.

Figure 1

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Plasma levels (pg/mL, picograms per milliliter) of VEGF (A), PlGF (B), sFlt-1 (C), and bFGF (D) in endurance-trained and sedentary men before and after acute exercise. Data are means±S.E.M.; sFlt-1, soluble fms-like tyrosine kinase-1; VEGF, vascular endothelial growth factor; bFGF, basic fibroblast growth factor; PlGF, placental growth factor

There were no significant interactions for TNF-α, IL-6 or IL-8 (P > 0.05 for each). TNF-α concentrations were not affected by acute exercise (Figure 2A; P > 0.05), but there was a main effect of acute exercise to increase IL-8 concentrations by 32% (1.3 ± 0.2 vs. 1.7 ± 0.2 pg/mL; Figure 2B; P < 0.05) and IL-6 concentrations by 165% (0.56 ± 0.14 vs. 1.3 ± 0.3 pg/mL; Figure 2C; P < 0.05). The main effect of training status (i.e., group main effect) on IL-8 approached statistical significance (P = 0.06). There were no statistically significant differences between groups in IL-6 or TNF-α either before or after acute exercise (Figure 2A and 2C).

Figure 2.

Figure 2

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Plasma levels (pg/mL, picograms per milliliter) of TNF-α (A), IL-8 (B), and IL-6 in endurance-trained and sedentary men before and after acute exercise. Data are means±S.E.M. TNF-α, tumor necrosis factor alpha; IL, interleukin.

There were no significant acute exercise-induced changes in percent hematocrit (45±0.58 vs. 47± 0.53 % groups combined) or hemoglobin concentration (15±0.22 vs. 16±0.19 % groups combined), indicating that these effects of acute exercise on plasma cytokine levels were not the result of exercise-induced shifts in plasma volume.

Discussion

Angiogenic and inflammatory cytokines play important roles in cell signaling in response to exercise-induced physiological stimuli (e.g., hypoxia and oxidative stress). Our major findings are that acute aerobic exercise increases circulating concentrations of the angiogenic cytokines PlGF, bFGF and sFlt-1, as well as IL-6 and IL-8 in both endurance-trained and sedentary young men. Overall, exercise-training status does not appear to significantly affect the circulating cytokine response to 30 minutes of acute exercise at the same relative exercise intensity.

Regular endurance exercise training is associated with lower levels of inflammatory markers in the basal state compared to pre-training levels (Gokhale et al. 2007; Gomes et al. 2012; Vassilakopoulos et al. 2002). Given these findings, we expected that levels of classic inflammatory markers TNF-α and IL-6 would be lower in endurance-trained subjects compared to their sedentary counterparts. Contrary to our hypothesis, we did not observe lower basal levels of inflammatory cytokines or an attenuated inflammatory response to the acute exercise stimulus in our endurance-trained subjects. Previous studies measuring plasma cytokines have shown that training status does not have a consistent effect on cytokine production in endurance-trained subjects compared to sedentary or recreationally-active subjects (Kraus 2004; Scott et al. 2013). In healthy populations, TNF-α production from muscle is stimulated by very intense or prolonged exercise (Nielsen and Pedersen 2007; Ostrowski et al. 1998), and the timing of the TNF-α response to exercise is variable. For instance, some suggest that the release of TNF-α may occur shortly after the onset of exercise and, thus, may not be detected in the circulation after even 30 minutes (Nielsen and Pedersen 2007; Ostrowski et al. 1998), while others have found that if TNF-α is released at all, this occurs more than 30 min after completion of the exercise bout (Febbraio and Pedersen 2002). IL-6 secretion as a result of exercise has been found to inhibit TNF-α (Febbraio and Pedersen 2002; Tanaka et al. 2001). Thus, if there was a true response of TNF-α in our subjects, the effect may have occurred only at the tissue level or the timing of our measurements was not optimal to detect changes due to interactions with other cytokines.

The presence of elevated IL-6 in circulation after exercise is established but few studies have assessed the effect of training status on IL-6 concentrations (Fischer 2004; Gokhale et al. 2007; Pedersen and Fischer 2007). Some have noted an attenuated IL-6 response to exercise in athletes compared to non-athletes (Gokhale et al. 2007), while others have found that 10 weeks of knee-extensor training resulted in no differences in plasma IL-6 concentrations in response to acute exercise, despite a 44% greater absolute workload (Fischer 2004). Similar to our study, these findings suggest no overall effect of exercise-training on the IL-6 response to acute exercise at the same relative intensity (Fischer 2004; Keller 2005; Pedersen and Fischer 2007). IL-6 has a vast array of biological properties including angiogenesis and vascular remodeling, as well as regulation of glucose homeostasis and fat oxidation (Pedersen and Fischer 2007). The noted post-exercise elevations may be indicative of metabolic influences of IL-6 that occur regardless of the subject’s training status (Nielsen and Pedersen 2007; Pedersen and Fischer 2007).

We observed a main effect of exercise with significantly increased IL-8 levels after exercise in both endurance-trained and sedentary subjects. Niemen et al. also found significantly higher IL-8 concentrations both immediately and 1 hour after completion of ~2 hours of cycling at 60% maximum work capacity in trained cyclists (Nieman et al. 2012). As IL-8 promotes angiogenesis (Heidemann 2002; Nielsen and Pedersen 2007), it is possible that these findings are indicative of an enhanced angiogenic stimulus with acute exercise, perhaps to a greater degree in endurance-trained subjects (Nielsen and Pedersen 2007). To our knowledge, previous investigations have not reported alterations in IL-8 concentrations as a result of subject training status, and the present study did not detect statistically significant differences in IL-8 as a function of training status.

Few studies have investigated the exercise-induced response of bFGF and PlGF. One investigation found no changes in bFGF concentrations after either high intensity or long-duration exercise, but there was considerable variation in individual peak bFGF responses to exercise (Wahl et al. 2010).Weissgerber et al. (2010) found no significant changes in serum PlGF concentrations following exercise in active or inactive women, although the blood sampling was significantly earlier than that of our study (Weissgerber et al. 2010). Contrary to these findings, we found that both bFGF and PlGF concentrations increased significantly in response to 30 minutes of running in both sedentary and endurance-trained men with no significant differences between groups. The exact role of PlGF in the angiogenic response to exercise remains unclear as PlGF deficient mice have reduced skeletal muscle capillary density in the untrained state, but a normal increase in capillary density in response to exercise training (Gigante et al. 2004).

Despite the main effect of time on bFGF, PlGF and sFlt-1, we found no significant changes in VEGF concentrations. The effects of acute exercise on plasma VEGF have produced conflicting results with some investigators finding an increase in peak VEGF levels after acute exercise (Kraus 2004; Wahl et al. 2010) and others finding no differences or decreases in VEGF in healthy subjects after prolonged or intense exercise (Adams 2004; Adams et al. 2008). It appears that the VEGF response is largely dependent on exercise intensity and a lack of consistency in study designs as far as exercise mode, intensity, duration, and timing of blood sampling after exercise may explain some of these discordant findings (Wahl et al. 2010). Others have found very early elevations in serum VEGF occurring within 10 minutes of the onset of exercise (Mobius-Winkler et al. 2009), or early increases within 10 minutes after the completion of acute exercise (Wahl et al. 2010) with levels returning to resting values shortly after peaking (Mobius-Winkler et al. 2009). Although the design of our study did not allow us to determine a time-course for cytokine levels, it is possible that VEGF levels increase early in response to exercise stimulating production of IL-6 (Mobius-Winkler et al. 2009), IL-8, or other cytokines but returning to resting levels by the time our samples were collected.

Plasma levels of sFlt-1 have previously been associated with VO2 peak during exercise (Bailey et al. 2006) suggesting that training status may have an effect on sFlt-1 concentrations. Our findings do not support this conclusion, but there was an effect of acute exercise to increase sFlt-1 concentrations. Bailey et al. also reported exercise-induced increases in plasma sFlt-1 in young, healthy males (Bailey et al. 2006). Their exercise-induced increases in sFlt-1 were associated with a transient decrease in circulating VEGF below resting values as early as 30 minutes after the cessation of exercise (Bailey et al. 2006). Our data support these findings in that we observed significant increases in plasma sFlt-1 concentrations in association with no changes in VEGF levels following 30 min of endurance exercise. We speculate that this association relates to the scavenging properties of sFlt-1 to maintain plasma VEGF within narrow physiological levels. Although beyond the scope of our current study, it is possible that circulating sFlt-1 plays a role in regulating non-specific angiogenic effects in some tissues by scavenging circulating VEGF and PlGF, while not affecting levels of these angiogenic factors locally in active tissues such as muscle.

Limitations

All subjects in our current study, regardless of training status, were young, healthy, and matched for BMI. Although there was a significant difference in percent body fat (7% vs. 15% in endurance trained vs. sedentary), the sedentary subjects were still in a healthy range of body composition (Medicine 2012). Given this, it is likely that the effects of regular exercise on resting cytokine levels as well as the cytokine responses to acute aerobic exercise may be more pronounced in a population with greater differences in adiposity and other CVD risk factors. The possibility of a type 2 error must also be acknowledged; it is possible that the sample size was insufficient to detect differences in cytokine levels between groups or conditions, particularly for the bFGF and IL-8 analyses. Differences in the duration, intensity and mode of acute exercise appear to be the major factors affecting the differential responses in our current investigation compared to others (Kraus 2004; Mobius-Winkler et al. 2009; Nieman et al. 2006; Ronsen et al. 2002; Scott et al. 2013; SCOTT et al. 2011; Vassilakopoulos et al. 2002). In our study, all subjects were exposed to the same relative exercise stimulus. Although this may not have produced sufficient increases in metabolic demands associated with the substantial cytokine responses observed by others (Pedersen and Fischer 2007), we utilized a standardized exercise protocol that reflects current guidelines for most young adults (Medicine 2012). Finally, the timing of measurements in the present study may not have been optimal to detect changes in certain cytokines such as VEGF and TNF-α. Thus, a comprehensive assessment of different exercise protocols and the timing of blood sampling is necessary to better define specific effects of angiogenic and inflammatory cytokines.

Conclusions

In summary, we found that acute exercise increases circulating levels of PlGF, bFGF, sFlt-1, IL-6 and IL-8. These results suggest that 30 minutes of treadmill running at 75% VO2 max provides an acute, systemic inflammatory and angiogenic stimulus, but chronic endurance exercise training does not appear to significantly alter the response to acute exercise in healthy young men.

Acknowledgements

This study was supported by the University of Maryland’s Kinesiology Graduate Research Initiative Fund (to NTJ), the Baltimore Veterans Affairs Medical Center Geriatric Research, Education and Clinical Center (GRECC), and the University of Maryland Claude D. Pepper Center (P30-AG028747). NTJ and RQL were supported by T32-AG200068 (to JMH), and SJP was supported by a Veterans Affairs Career Development Award and is currently supported by K23-AG040775.

Abbreviations

ACSM

American College of Sports Medicine

bFGF

basic fibroblast growth factor

BMI

body mass index

CV

cardiovascular

ELISA

enzyme-linked immunosorbent assay

IL

interleukin

NSAIDs

non-steroidal anti-inflammatory drugs

PlGF

placental growth factor

sFlt-1

soluble fms-like tyrosine kinase-1

TNF-α

tumor necrosis factor- alpha

VEGF

vascular endothelial growth factor

VO2max

maximal oxygen uptake

Footnotes

Author Contributions: NTJ, ES, JH, and SJP conceived and designed the research. RQL, NTJ, and SJP performed the experiments and analyzed the data. All authors interpreted the results of the experiments. RQL drafted the manuscript; NTJ, ES, JH, and SJP edited and revised the manuscript. All authors approved the final version of the manuscript

Conflict of Interest

The authors have no conflicts of interest to declare

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