Aerobically trained older adults show impaired resting, but preserved exercise-induced circulating progenitor cell count, which was not improved by sprint interval training.

Older adults exhibit a reduced number and function of CD34 + circulating progenitor cells (CPC), a known risk factor for cardiovascular disease. Exercise promotes the mobilisation of CPCs from bone marrow, so whether ageing per se or physical inactivity in older age reduces CPCs is unknown. Thus, this study examined the effect of age on resting and exercise-induced changes in CPCs in aerobically trained adults and the effect of 8 weeks of sprint interval training (SIT) on resting and exercise-induced CPCs in older adults. Twelve young (22-34 years) and nine older (63-70 years) adults participated in the study. Blood was sampled pre and immediately post a graded exercise test to exhaustion in both groups. Older participants repeated the process after 8 weeks of SIT (3 × 20 s 'all-out' sprints, 2 × a week). Total CPCs (CD34+) and endothelial progenitor cells (EPCs: CD34+KDR+) were determined by flow cytometry. Older adults exhibited lower basal total CD34+ CPCs (828 ± 314 vs. 1186 ± 272 cells·mL-1, p = 0.0149) and CD34+KDR+ EPCs (177 ± 128 vs. 335 ± 92 cells·mL-1, p = 0.007) than younger adults. The maximal exercise test increased CPCs in young (CD34+: p = 0.004; CD34+KDR+: p = 0.017) and older adults (CD34+: p < 0.001; CD34+KDR+: p = 0.008), without difference between groups (p = 0.211). SIT did not alter resting or exercise-induced changes in CPCs in the older cohort (p > 0.232). This study suggests age per se does not impair exercise-induced CPC counts, but does lower resting CPC counts.

Type 1 Diabetes Patients With Different Residual Beta-Cell Function but Similar Age, HBA1c, and Cardiorespiratory Fitness Have Differing Exercise-Induced Angiogenic Cell Mobilisation.

Background: Many individuals with type 1 diabetes retain residual beta-cell function. Sustained endogenous insulin and C-peptide secretion is associated with reduced diabetes related complications, but underlying mechanisms remain unclear. Lower circulating numbers of endothelial and hematopoietic progenitor cells (EPCs and HPCs), and the inability to increase the count of these cells in response to exercise, are also associated with increased diabetes complications and cardiovascular disease. It is unknown whether residual beta-cell function influences HPCs and EPCs. Thus, this study examined the influence of residual beta-cell function in type 1 diabetes upon exercise-induced changes in haematopoietic (HPCs) and endothelial progenitor cells (EPCs). Methods: Participants with undetectable stimulated C-peptide (n=11; Cpepund), 10 high C-peptide (Cpephigh; >200 pmol/L), and 11 non-diabetes controls took part in this observational exercise study, completing 45 minutes of intensive walking at 60% V˙O2peak . Clinically significant HPCs (CD34+) and EPCs (CD34+VEGFR2+) phenotypes for predicting future adverse cardiovascular outcomes, and subsequent cell surface expression of chemokine receptor 4 (CXCR4) and 7 (CXCR7), were enumerated at rest and immediately post-exercise by flow cytometry. Results: Exercise increased HPCs and EPCs phenotypes similarly in the Cpephigh and control groups (+34-121% across phenotypes, p<0.04); but Cpepund group did not significantly increase from rest, even after controlling for diabetes duration. Strikingly, the post-exercise Cpepund counts were still lower than Cpephigh at rest. Conclusions: Residual beta-cell function is associated with an intact exercise-induced HPCs and EPCs mobilisation. As key characteristics (age, fitness, HbA1c) were similar between groups, the mechanisms underpinning the absent mobilisation within those with negative C-peptide, and the vascular implications, require further investigation.

CD34+ progenitors are predictive of mortality and are associated with physical activity in cardiovascular disease patients.

BACKGROUND AND AIMS: Circulating progenitor cells (CPCs) play an important role in vascular repair and can influence cardiovascular (CV) health and longevity. Exercise is known to modulate these cells via mobilization from the bone marrow. The primary aims of this study were to evaluate the association of CPCs with mortality and explore the association between physical activity (PA) and CPCs. METHODS: 1751 individuals from the Framingham Offspring cohort (66 ± 9 years [40-92 years], 54% female) were included in the study. CPCs (CD34+, CD34+CD133+, CD34+CD133+KDR+) were measured by flow cytometry. Multivariable Cox regression analyses were performed to investigate relationship of CPCs with future CV event and mortality. Multivariate regression analyses were performed to determine the relationship between self-reported PA and CPC counts. RESULTS: Following adjustment for standard risk factors, there was an inverse association between CD34+ CPCs and all-cause mortality (hazard ratio (HR) per unit increase in CD34+, 0.79; 95% CI 0.64-0.98, p = 0.036). CD34+CD133+ CPCs were inversely associated with CV mortality (HR 0.63, 95% CI 0.44-0.91, p = 0.013). Associations of CD34+ and CD34+CD133+ with mortality were strongest in participants with pre-existing CVD. PA was associated with CD34+ CPCs only in CVD participants (PA Index: ß = 0.176, p = 0.003; moderate-to-vigorous [MVPA]: ß = 0.159, p = 0.007). This relationship was maintained after adjustment for confounding variables. CONCLUSIONS: A higher number of CD34+ and CD34+ CD133+ CPCs was inversely associated with all-cause and CV mortality. These associations were strongest in participants with CVD. PA is independently associated with CD34+ CPCs in individuals with CVD only, suggestive of greater benefit for this population group.

The Role of MSC Therapy in Attenuating the Damaging Effects of the Cytokine Storm Induced by COVID-19 on the Heart and Cardiovascular System.

The global pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19) has led to 47 m infected cases and 1. 2 m (2.6%) deaths. A hallmark of more severe cases of SARS-CoV-2 in patients with acute respiratory distress syndrome (ARDS) appears to be a virally-induced over-activation or unregulated response of the immune system, termed a "cytokine storm," featuring elevated levels of pro-inflammatory cytokines such as IL-2, IL-6, IL-7, IL-22, CXCL10, and TNFα. Whilst the lungs are the primary site of infection for SARS-CoV-2, in more severe cases its effects can be detected in multiple organ systems. Indeed, many COVID-19 positive patients develop cardiovascular complications, such as myocardial injury, myocarditis, cardiac arrhythmia, and thromboembolism, which are associated with higher mortality. Drug and cell therapies targeting immunosuppression have been suggested to help combat the cytokine storm. In particular, mesenchymal stromal cells (MSCs), owing to their powerful immunomodulatory ability, have shown promise in early clinical studies to avoid, prevent or attenuate the cytokine storm. In this review, we will discuss the mechanistic underpinnings of the cytokine storm on the cardiovascular system, and how MSCs potentially attenuate the damage caused by the cytokine storm induced by COVID-19. We will also address how MSC transplantation could alleviate the long-term complications seen in some COVID-19 patients, such as improving tissue repair and regeneration.

Vascular Manifestations of COVID-19 - Thromboembolism and Microvascular Dysfunction.

The coronavirus pandemic has reportedly infected over 31.5 million individuals and caused over 970,000 deaths worldwide (as of 22nd Sept 2020). This novel coronavirus, officially named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), although primarily causes significant respiratory distress, can have significant deleterious effects on the cardiovascular system. Severe cases of the virus frequently result in respiratory distress requiring mechanical ventilation, often seen, but not confined to, individuals with pre-existing hypertension and cardiovascular disease, potentially due to the fact that the virus can enter the circulation via the lung alveoli. Here the virus can directly infect vascular tissues, via TMPRSS2 spike glycoprotein priming, thereby facilitating ACE-2-mediated viral entry. Clinical manifestations, such as vasculitis, have been detected in a number of vascular beds (e.g., lungs, heart, and kidneys), with thromboembolism being observed in patients suffering from severe coronavirus disease (COVID-19), suggesting the virus perturbs the vasculature, leading to vascular dysfunction. Activation of endothelial cells via the immune-mediated inflammatory response and viral infection of either endothelial cells or cells involved in endothelial homeostasis, are some of the multifaceted mechanisms potentially involved in the pathogenesis of vascular dysfunction within COVID-19 patients. In this review, we examine the evidence of vascular manifestations of SARS-CoV-2, the potential mechanism(s) of entry into vascular tissue and the contribution of endothelial cell dysfunction and cellular crosstalk in this vascular tropism of SARS-CoV-2. Moreover, we discuss the current evidence on hypercoagulability and how it relates to increased microvascular thromboembolic complications in COVID-19.

Circulating angiogenic cell response to sprint interval and continuous exercise.

INTRODUCTION: Although commonly understood as immune cells, certain T lymphocyte and monocyte subsets have angiogenic potential, contributing to blood vessel growth and repair. These cells are highly exercise responsive and may contribute to the cardiovascular benefits seen with exercise. PURPOSE: To compare the effects of a single bout of continuous (CONTEX) and sprint interval exercise (SPRINT) on circulating angiogenic cells (CAC) in healthy recreationally active adults. METHODS: Twelve participants (aged 29 ± 2 years, BMI 25.5 ± 0.9 kg m- 2, [Formula: see text]peak 44.3 ± 1.8 ml kg- 1 min- 1; mean ± SEM) participated in the study. Participants completed a 45-min bout of CONTEX at 70% peak oxygen uptake and 6 × 20 s sprints on a cycle ergometer, in a counterbalanced design. Blood was sampled pre-, post-, 2 h and 24 h post-exercise for quantification of CAC subsets by whole blood flow cytometric analysis. Angiogenic T lymphocytes (TANG) and angiogenic Tie2-expressing monocytes (TEM) were identified by the expression of CD31 and Tie2, respectively. RESULTS: Circulating (cells µL- 1) CD3+CD31+ TANG increased immediately post-exercise in both trials (p < 0.05), with a significantly greater increase (p < 0.05) following SPRINT (+ 57%) compared to CONTEX (+ 14%). Exercise increased (p < 0.05) the expression of the chemokine receptor CXCR4 on TANG at 24 h. Tie2-expressing classical (CD14++CD16-), intermediate (CD14++CD16+) and non-classical (CD14+CD16++) monocytes and circulating CD34+CD45dim progenitor cells were higher post-exercise in SPRINT, but unchanged in CONTEX. All post-exercise increases in SPRINT were back to pre-exercise levels at 2 h and 24 h. CONCLUSION: Acute exercise transiently increases circulating TANG, TEM and progenitor cells with greater increases evident following very high intensity sprint exercise than following prolonged continuous paced endurance exercise.

An acute dose of inorganic dietary nitrate does not improve high-intensity, intermittent exercise performance in temperate or hot and humid conditions.

PURPOSE: Dietary nitrate (NO3-) has repeatedly been shown to improve endurance and intermittent, high-intensity events in temperate conditions. However, the ergogenic effects of dietary NO3- on intermittent exercise performance in hot conditions have yet to be investigated. METHODS: In a randomised, counterbalanced, double-blind crossover study, 12 recreationally trained males ingested a nitrate-rich beetroot juice shot (BRJ) (6.2 mmol NO3-) or a nitrate-depleted placebo (PLA) (< 0.004 mmol NO3-) 3 h prior to an intermittent sprint test (IST) in temperate (22 °C, 35% RH) and hot conditions (30 °C, 70% RH). The cycle ergometer IST consisted of twenty maximal 6 s sprints interspersed by 114 s of active recovery. Work done, power output, heart rate and RPE were measured throughout; tympanic temperature was measured prior to and upon completion. RESULTS: There were no significant effects of supplement on sprint performance in either temperate or hot, humid conditions (p > 0.05). There was a reduced peak (BRJ: 659 ± 100W vs. PLA: 693 ± 139W; p = 0.056) and mean power (BRJ: 543 ± 29W vs. PLA: 575 ± 38W; p = 0.081) following BRJ compared to PLA in the hot and humid condition, but this was not statistically significant. There was no effect of supplement on total work done irrespective of environmental condition. However, ~ 75% of participants experienced performance decreases following BRJ in the hot and humid environment. No differences were observed between trials for tympanic temperature measured at the conclusion of the exercise trial. CONCLUSION: In conclusion, an acute dose of inorganic dietary NO3- does not improve repeated-sprint performance in either temperate, or hot and humid conditions.

Endothelial Regenerative Capacity and Aging: Influence of Diet, Exercise and Obesity.

BACKGROUND: The endothelium plays an important role in cardiovascular regulation, from blood flow to platelet aggregation, immune cell infiltration and demargination. A dysfunctional endothelium leads to the onset and progression of Cardiovascular Disease (CVD). The aging endothelium displays significant alterations in function, such as reduced vasomotor functions and reduced angiogenic capabilities. This could be partly due to elevated levels of oxidative stress and reduced endothelial cell turnover. Circulating angiogenic cells, such as Endothelial Progenitor Cells (EPCs) play a significant role in maintaining endothelial health and function, by supporting endothelial cell proliferation, or via incorporation into the vasculature and differentiation into mature endothelial cells. However, these cells are reduced in number and function with age, which may contribute to the elevated CVD risk in this population. However, lifestyle factors, such as exercise, physical activity obesity, and dietary intake of omega-3 polyunsaturated fatty acids, nitrates, and antioxidants, significantly affect the number and function of these circulating angiogenic cells. CONCLUSION: This review will discuss the effects of advancing age on endothelial health and vascular regenerative capacity, as well as the influence of diet, exercise, and obesity on these cells, the mechanistic links and the subsequent impact on cardiovascular health.

Lower resting and exercise-induced circulating angiogenic progenitors and angiogenic T cells in older men.

Aging is associated with a dysfunctional endothelial phenotype as well as reduced angiogenic capabilities. Exercise exerts beneficial effects on the cardiovascular system, possibly by increasing/maintaining the number and/or function of circulating angiogenic cells (CACs), which are known to decline with age. However, the relationship between cardiorespiratory fitness (CRF) and age-related changes in the frequency of CACs, as well as the exercise-induced responsiveness of CACs in older individuals, has not yet been determined. One-hundred seven healthy male volunteers, aged 18-75 yr, participated in study 1. CRF was estimated using a submaximal cycling ergometer test. Circulating endothelial progenitor cells (EPCs), angiogenic T cells (TANG), and their chemokine (C-X-C motif) receptor 4 (CXCR4) cell surface receptor expression were enumerated by flow cytometry using peripheral blood samples obtained under resting conditions before the exercise test. In study 2, 17 healthy men (8 young men, 18-25 yr; 9 older men, 60-75 yr) were recruited, and these participants undertook a 30-min cycling exercise bout at 70% maximal O2 consumption, with CACs enumerated before and immediately after exercise. Age was inversely associated with both CD34+ progenitor cells ( r2 = -0.140, P = 0.000) and TANG ( r2 = -0.176, P = 0.000) cells as well as CXCR4-expressing CACs (CD34+: r2 = -0.167, P = 0.000; EPCs: r2 = -0.098, P = 0.001; TANG: r2 = -0.053, P = 0.015). However, after correcting for age, CRF had no relationship with either CAC subset. In addition, older individuals displayed attenuated exercise-induced increases in CD34+ progenitor cells, TANG, CD4+, TANG, and CD8+CXCR4+ TANG cells. Older men display lower CAC levels, which may contribute to increased risk of cardiovascular disease, and older adults display an impaired exercise-induced responsiveness of these cells. NEW & NOTEWORTHY Older adults display lower circulating progenitor cell and angiogenic T cell counts compared with younger individuals independently of cardiometabolic risk factors and cardiorespiratory fitness. Older adults also display impaired exercise-induced mobilization of these vasculogenic cells.

Influence of a low-carbohydrate diet on endothelial microvesicles in overweight women.

Low-carbohydrate diets (LCD) are increasing in popularity, but their effect on vascular health has been questioned. Endothelial microvesicles (EMV) are membrane-derived vesicles with the potential to act as a sensitive prognostic biomarker of vascular health and endothelial function. The aim of this study was to examine the influence of a LCD on EMV and other endothelial biomarkers of protein origin. Twenty-four overweight women (age, 48.4 ± 0.6 years; height, 1.60 ± 0.07 m; body mass, 76.5 ± 9.1 kg; body mass index, 28.1 ± 2.7 kg·m(-2); waist circumference, 84.1 ± 7.4 cm; mean ± standard deviation) were randomised to either 24 weeks on their normal diet (ND) or a LCD, after which they crossed over to 24 weeks on the alternative diet. Participants were assisted in reducing carbohydrate intake, but not below 40 g·day(-1). Body composition and endothelial biomarkers were assessed at the crossover point and at the end of the study. Daily carbohydrate intake (87 ± 7 versus 179 ± 11 g) and the percentage of energy derived from carbohydrate (29% versus 44%) were lower (p < 0.05) on the LCD compared to the ND, but absolute fat and saturated fat intake were unchanged. Body mass and waist circumference were 3.7 ± 0.8 kg and 3.5 ± 1.0 cm lower (p < 0.05), respectively, after the LCD compared with the ND phases. CD31(+)CD41(-)EMV, soluble (s) thrombomodulin, sE-selectin, sP-selectin, serum amyloid A and C-reactive protein were lower (p < 0.05) after the LCD compared to the ND, but serum lipids and apolipoproteins were not different. EMV along with a range of endothelial and inflammatory biomarkers are reduced by a LCD that involves modest weight loss.

Vascular Ageing and Exercise: Focus on Cellular Reparative Processes.

Ageing is associated with an increased risk of developing noncommunicable diseases (NCDs), such as diabetes and cardiovascular disease (CVD). The increased risk can be attributable to increased prolonged exposure to oxidative stress. Often, CVD is preceded by endothelial dysfunction, which carries with it a proatherothrombotic phenotype. Endothelial senescence and reduced production and release of nitric oxide (NO) are associated with "vascular ageing" and are often accompanied by a reduced ability for the body to repair vascular damage, termed "reendothelialization." Exercise has been repeatedly shown to confer protection against CVD and diabetes risk and incidence. Regular exercise promotes endothelial function and can prevent endothelial senescence, often through a reduction in oxidative stress. Recently, endothelial precursors, endothelial progenitor cells (EPC), have been shown to repair damaged endothelium, and reduced circulating number and/or function of these cells is associated with ageing. Exercise can modulate both number and function of these cells to promote endothelial homeostasis. In this review we look at the effects of advancing age on the endothelium and these endothelial precursors and how exercise appears to offset this "vascular ageing" process.

Resistance exercise increases endothelial progenitor cells and angiogenic factors.

INTRODUCTION: Bone marrow-derived endothelial progenitor cells (EPC) are involved in vascular growth and repair. They increase in the circulation after a single bout of aerobic exercise, potentially related to muscle ischemia. Muscular endurance resistance exercise (MERE) bouts also have the potential to induce muscle ischemia if appropriately structured. PURPOSE: The objective of this study is to determine the influence of a single bout of MERE on circulating EPC and related angiogenic factors. METHODS: Thirteen trained men age 22.4 ± 0.5 yr (mean ± SEM) performed a bout of MERE consisting of three sets of six exercises at participants' 15-repetition maximum without resting between repetitions or exercises. The MERE bout duration was 12.1 ± 0.6 min. Blood lactate and HR were 11.9 ± 0.9 mmol·L and 142 ± 5 bpm, respectively, at the end of MERE. Blood was sampled preexercise and at 10 min, 2 h, and 24 h postexercise. RESULTS: Circulating EPC and serum concentrations of vascular endothelial growth factors (VEGF-A, VEGF-C, and VEGF-D), granulocyte colony stimulating factor, soluble Tie-2, soluble fms-like tyrosine kinase-1, and matrix metalloproteinases (MMP-1, MMP-2, MMP-3, MMP-9, and MMP-9) were higher (P < 0.05) in the postexercise period. Circulating EPC levels were unchanged at 10 min postexercise but higher at 2 h postexercise (P < 0.05). The concentration of most angiogenic factors and metalloproteinases were higher at 10 min postexercise (VEGF-A, +38%; VEGF-C, +40%; VEGF-D, +9%; soluble Tie-2, +15%; soluble fms-like tyrosine kinase-1, +24%; MMP-1, +62%; MMP-2, +3%; MMP-3, +54%; and MMP-9, +45%; all P < 0.05). Soluble E-selectin was lower (P < 0.05) at 2 and 24 h postexercise, with endothelial microparticles and thrombomodulin unchanged. CONCLUSIONS: Short intense bouts of MERE can trigger increases in circulating EPC and related angiogenic factors, potentially contributing to vascular adaptation and vasculoprotection.