Endothelial Progenitor Cells Concentrations Research Articles

CLINICAL CONSEQUENCES IN POST COVID-19 HYPERTENSIVE PATIENTS

Objective: to evaluate the clinical consequences in hypertensive patients after 1.2 ± 0.3 years after COVID-19 recovery. Design and method: We studied 51 treated hypertensive patients, which were divided into 2 groups: 26 patients recovered from mild to moderate COVID-19 in 2020-2021 years (1st group) and 25 patients were not ill COVID-19 (2nd group). The clinical characteristics, laboratory finding, echocardiographic measurement and clinical outcomes were analyzed. Results: There were no significant differences in sex, age, duration of hypertension, frequency of family history of premature CVD and presence of concomitant obesity, DM, CAD, stroke/TIA, atrial fibrillation, heart failure, CKD, PAD and average number of antihypertensive drugs, office systolic BP between the 2 groups. Levels of office diastolic BP by 10 % (P = 0.001) and heart rate by 13 % (P = 0.01) were higher in post COVID-19 group. Low adherence was present at 81.8 % patients 1st group compared with 45 % of 2nd patients group (P = 0.03). Cognitive impairment by the MMSE scale was detected in 68.2 % of COVID-19 recovered patients and 25 % of 2nd patients group (P = 0.03). Fasting glucose by 7.5 % (P = 0.046), 24-h albuminuria in 1.8 times (P = 0.049), level of CRP by 38.5 % (P = 0.04) were higher and blood concentration of endothelial progenitor cells (CD133+CD31+CD45-/+) by 14, 9 % (P = 0.04), left ventricular ejection fraction by 10 % (P = 0.03) were lower in post COVID-19 patients than in patients of 2nd group. Conclusions: The study indicate that the changes were found in the hypertensive patients after 1.2 ± 0.3 years of recovery from COVID-19. In the future these may signal an increased risk for incidence of CV outcomes. Cognitive dysfunction and possibly as a consequence poor adherence to antihypertensive treatment contribute to negative outcomes.

CARDIOVASCULAR AND KIDNEY OUTCOMES IN TREATED RESISTANT HYPERTENSIVE PATIENTS

Objective: To evaluate the incidence of cardiovascular (CV) and kidney outcomes and its predictors in treated resistant hypertensive (rHTN) patients. Design and method: We studied 117 rHTN patients and 114 controlled hypertensives (cHTN) patients on a triple fixed-dose combination of RAAS blockers / CCB / thiazide or thiazide-like diuretic. Patients with rHTN treated with the same type of triple fixed-dose combination in maximally tolerated doses plus the individually defined most effective fourth-line agent (spironolactone/eplerenone 56.1%, torasemide 26.8%, nebivolol 14.6%, moxonidine 2.5%); the fifth class of antihypertensive drug was added for 35.2 % of patients. A composite CV (CV death, myocardial infarction and/or revascularization, stroke, atrial fibrillation, and peripheral arterial disease) and kidney outcome (dialysis or GFR decline by 40% or greater) were estimated after five years (a mean follow-up 5.1 ± 0.1). The combined endpoint was defined as total CV and renal outcome events. Results: The goal office and 24-h BP were achieved at 49.6 and 34.2 % rHTN patients by the end of 5-year follow-up. During follow-up the incidence of all outcomes were higher at rHTN patients compared to cHTN pts: composite CV events (26.5 % vs 7 %, P = 0.001), kidney outcomes (4.3 % vs 0.9 %, P = 0.01), and diabetes (3.4 % vs 0.9 %, P = 0.02). The independent predictors of combined end point identified by multivariant logistic regression analysis were initial 24-h systolic BP ( = 0.099; OR = 1.10; 95 % CI 1.03 – 1.18; P = 0.008), blood concentration of endothelial progenitor cells (CD45+/CD34+) ( = - 0.89; OR = 0.41; 95 % CI: 0.21 – 0.79), P = 0.007) and citrulline ( = - 0.89; OR = 1.13; 95 % CI: 1.07 – 1.20; P < 0.001). Conclusions: Despite significant improvement in BP control the incidence of CV and renal outcomes in rHTN patients were higher than in cHTN patients. The independent predictors of combined CV and renal events were higher baseline systolic blood pressure, citrulline plasma level, and low concentration of endothelial progenitor cells.

Mobilized and apheresis-collected endothelial progenitor cells with plerixafor.

Endothelial progenitor cells (EPCs) are immature cells able to proliferate and contribute to endothelial repair, vascular homeostasis, neovascularization, and angiogenesis. It therefore seems likely that circulating EPCs have therapeutic potential in ischemic and vascular diseases. In this study we evaluated the efficiency of EPC mobilization and collection by large volume leukapheresis in subjects with hematological diseases, treated with plerixafor in association with G-CSF. Twenty-two patients with lymphoid malignancies underwent rHuG-CSF and plerixafor treatment followed by leukapheresis. Blood samples before and after treatment and apheresis liquid sample were taken and analyzed by flow cytometry in order to quantified EPC. The percentage of CD34+ cells and EPCs among circulating total nuclear cells (TNCs) increased significantly by approximately 2-fold and 3-fold, respectively, after plerixafor treatment. Consequently, the absolute number of CD34+ cells and EPCs were increased 4-fold after plerixafor treatment. The median PB concentration of EPCs before and after treatment were 0.77/μL (0.31-2.15) and 3.41/μL (1.78-4.54), respectively, P< .0001. The total EPCs collected per patient were 3.3×107 (0.8×107 -6.8×107 ). We have shown that plerixafor in combination with G-CSF allows the mobilization and collection of large amounts of EPCs along with CD34+ cells in lymphoid neoplasm patients. The possibility to collect and to store these cells could represent a promising therapeutic tool for the treatment of ischemic complications without the need of in vitro expansion.

Evaluation of endothelial function and subclinical atherosclerosis in patients with HIV infection

The aim of this study was to analyse the association between human immunodeficiency virus (HIV) related clinical and analytical parameters and the presence of subclinical atherosclerosis as well as endothelial dysfunction. This was a prospective cohort study of HIV-positive patients who underwent intima media thickness (IMT) determination and coronary artery calcium scoring to determine subclinical atherosclerosis. To detect endothelial dysfunction, the breath holding index, flow-mediated dilation and the concentration of endothelial progenitor cells (EPCs) were measured. Patients with an IMT ≥ 0.9 mm had an average of 559.3 ± 283.34 CD4/μl, and those with an IMT < 0.9 mm had an average of 715.4 ± 389.92 CD4/μl (p = 0.04). Patients with a low calcium score had a significantly higher average CD4 cell value and lower zenith viral load (VL) than those with a higher score (707.7 ± 377.5 CD4/μl vs 477.23 ± 235.7 CD4/μl (p = 0.01) and 7 × 104 ± 5 × 104 copies/ml vs 23.4 × 104 ± 19 × 104 copies/ml (p = 0.02)). The number of early EPCs in patients with a CD4 nadir < 350/µl was lower than that in those with a CD4 nadir ≥ 350 (p = 0.03). In HIV-positive patients, low CD4 cell levels and high VL were associated with risk of developing subclinical atherosclerosis. HIV patients with CD4 cell nadir < 350/µl may have fewer early EPCs.

Increased circulating endothelial progenitor cells (EPCs) in prepubertal children born prematurely: a possible link between prematurity and cardiovascular risk.

Endothelial progenitor cells (EPCs) ensure vascular integrity and neovascularization. No studies have investigated EPCs in preterm-born children beyond infancy. One hundred and thirty-six prepubertal children were enrolled: 63 preterm and 73 born at term (controls). Circulating CD34(+)/VEGFR-2(+)/CD45(-) and CD34(+)/VEGFR-2(+)/CD45dim EPCs were measured in preterm-born children compared to controls. Body mass index (BMI), waist-to-hip ratio (WHR), neck circumference, systolic and diastolic blood pressure (SBP and DBP, respectively), fasting glucose, insulin, lipid profile, common carotid and abdominal aortic intima-media thickness (cIMT and aIMT, respectively), endothelium-dependent brachial artery flow-mediated dilation (FMD), and echocardiographic parameters were also assessed. Circulating CD34(+)/VEGFR-2(+)/CD45(-) and CD34(+)/VEGFR-2(+)/CD45dim EPCs were significantly higher in preterm-born children compared to controls (p < 0.001 and p < 0.001, respectively). In total study population and in the preterm-born group, EPCs were significantly lower in children born to mothers with gestational diabetes compared to non-diabetic mothers. Prematurity was associated with higher WHR, neck circumference, SBP, DBP, cIMT, aIMT, mean pressure, and velocity of pulmonary artery; the peak velocity of the brachial artery was significantly lower in children born prematurely. In multiple regression analysis, preterm birth and maternal gestational diabetes were recognized as independent predictors of EPCs. Circulating EPCs were increased in prepubertal preterm-born children in comparison with peers born full-term. Maternal gestational diabetes was associated with a decrease in EPCs. Mounting evidence supports the adverse effect of prematurity on cardiovascular health. However, the underlying mechanisms that could lead to endothelial dysfunction in preterm-born individuals are not fully understood. Endothelial progenitor cells (EPCs) ensure vascular integrity, normal endothelial function and neovascularization. No studies have investigated the EPCs counts in peripheral blood beyond infancy in children born prematurely. Circulating EPCs were significantly higher in preterm-born prepubertal children compared to controls, thus indicating that prematurity is possibly associated with endothelial damage. In total study population and in the preterm-born group, maternal gestational diabetes was associated with decreased EPCs concentrations.

The Role of The G Protein Coupled Estrogen Receptor in Endothelial Progenitor Cell Number and Function

Microvascular dysfunction is a key component of cardiovascular disease and plasma estrogen levels have been shown to impact vascular function. Endothelial progenitor cells (EPCs) are a stem cell population that support the integrity of the microvasculature and show increased proliferation in response to estradiol exposure when assessed in vitro. The plasma concentration of EPCs negatively correlates with incidence of stroke and coronary artery disease. In vivo studies of the effect of estradiol exposure on EPC number are complicated by the presence of other estrogens and complex estrogen signaling pathways. In EPCs, pathways that are activated via nuclear estrogen receptors are well investigated and pro‐angiogenic. Recent evidence suggests that other estrogens may be biologically active through a G protein coupled estrogen receptor, GPER, and that activation of GPER may have a modulatory relationship with nuclear estrogen receptor pathways. Investigation of GPER in EPCs is crucial to understanding the effects of estrogens on EPC health and vascular function.Here, we present the first evidence that GPER is present in human EPCs via immunohistochemistry and PCR analysis. We also investigated the role of agonism and antagonism of GPER in human EPC proliferation, migration, adhesion and paracrine function. Human EPCs were defined as cells that are isolated from bone marrow or peripheral blood mononuclear cell fractions, display typical endothelial cell (EC) morphology and are positive for cell surface proteins: VEGFR2, CD133, cKIT, CD34, and Dil‐ac‐LDL uptake. We assessed GPER expression via qPCR and immunocytochemistry on EPCs without hormone treatment. The proliferation assays were performed over a 24 hour exposure to 100 nM estradiol in combination with one of the following: 0.1, 1 and 10 μM concentrations of GPER agonist, G1 or GPER antagonist, G36. In our migration, adhesion and proliferation assays, EPCs were exposed to 100 nM estradiol in combination with one of the GPER modulator concentrations (as described above) for 24 hours and assessed thereafter. Migration was assessed via Transwell migration assay. To assay adhesion 1000 EPCs were seeded onto a 96 well plate, incubated for 4 hours and rinsed. Wells were then imaged and adherent cells were quantified. EPC paracrine function was assessed by tube formation assay. In this assay, treated EPCs were added to an endothelial cell tube formation assay to assess their ability to augment endothelial cell tubulogenesis.Our results show that GPER is expressed on human EPCs. In vitro EPC proliferation, migration, adhesion and paracrine function was enhanced by antagonism of GPER in a dose dependent manner. In vitro EPC proliferation, migration, adhesion and paracrine function was attenuated by agonism of GPER in a dose dependent manner. To investigate candidates for activators of this modulatory pathway, further studies will investigate estrone, the most prominent estrogen in males and postmenopausal females, and its action at GPER.

The Role of Estrone in Endothelial Progenitor Cell Number and Function

Microvascular dysfunction is a key component of cardiovascular disease and estrogens, particularly estradiol, have been shown to be vascular protective. Endothelial progenitor cells (EPCs) are a stem cell population that supports the integrity of the microvasculature and show increased proliferation in response to estradiol exposure. The plasma concentration of EPCs negatively correlates with incidence of stroke and coronary artery disease. Another estrogen, estrone, has been understudied due to its weak binding at nuclear estrogen receptors ERa and ERb. However, recent evidence suggests that estrone is biologically active through a G protein coupled estrogen receptor, GPER. In some vascular cell populations, estrone independently increases proliferation and modulates the proliferative effects of estradiol. In pre‐menopausal women with high estradiol/estrone ratio, EPCs are present in sufficient numbers to enhance angiogenesis and repair vessels at sites of damage. After menopause when the estradiol/estrone ratio is low, EPC number is decreased, the microvasculature is compromised, and CVD risk increases. In the treatment of symptoms of menopause, we use a combination estrogen therapy which is largely estrone based. Using this therapy, estradiol levels are restored pharmacologically, but the estradiol/estrone ratio remains low. During treatment, EPC numbers remain low and cardiovascular risk remains high.Here we investigate the role of estrone in EPC proliferation via in vitro exposure studies using EPCs from human female blood samples and EPCs isolated from the bone marrow of Sprague Dawley Rats. We also assess how estrone, estradiol and combination exposures effect the ability of EPCs to enhance endothelial cell tube formation (vasculogenesis in vitro). Human and rat EPCs were defined as cells derived from the mononuclear cell fraction that after 10–14 days of expansion/selection in culture adhere to fibronectin, display typical endothelial cell (EC) morphology and are positive for the EPC markers VEGFR2, CD133, cKIT, CD34, and Dil‐ac‐LDL uptake. After sample collection (human peripheral blood or rat bone marrow), the mononuclear cell layer was isolated using density centrifugation. The mononuclear cell layer was then plated in endothelial growth media for 14 days. After 14 days the EPCs cells were used for expression, proliferation and tube formation assays. The proliferation assays were performed over a 24 hour exposure to 1 &amp; 2 nmol estrone, 1 &amp; 2 nmol estradiol and 1:1 (1nmol) estrone:estradiol. In our tube formation assay, EPCs were exposed to estrone, estradiol and 1:1 estrone:estradiol for 24 hours and then added to an endothelial cell tube formation assay. We assessed GPER expression via qPCR and immunocytochemistry on EPCs without hormone treatment.In vitro EPC proliferation was enhanced by both estrone and estradiol in a dose dependent manner. When estrone and estradiol were applied in a one to one ratio, resulting EPC proliferation was below that of control. GPER is expressed on both human and rat EPCs. Further studies will use a rat model to investigate physiological effects of estrone and GPER agonism on EPC ability to enhance angiogenesis in vivo.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Active Stromal Cell-Derived Factor 1α and Endothelial Progenitor Cells are Equally Increased by Alogliptin in Good and Poor Diabetes Control.

Background:It is postulated that the ability of dipeptidyl peptidase-4 inhibitors (DPP-4-i) to increase circulating endothelial progenitor cells (EPCs) may be at least partly mediated by active stromal cell–derived factor 1α (SDF-1α) (a pivotal mediator of stem cell mobilization from the bone marrow). As other DPP-4-i were demonstrated to increase EPC concentrations, in this study, we sought to investigate the ability of the DPP-4-i alogliptin in modifying EPCs and SDF-1α, in patients with good and poor diabetes control.Methods:Two groups of diabetic patients on metformin were divided by hemoglobin A1c (HbA1c): Group A—those with HbA1c ≤6.5% (28 patients) and Group B—those with HbA1c 7.5% to 8.5% (31 patients). Both groups received alogliptin 25 mg/daily for 4 months. At baseline and 4 months later, clinical, laboratory parameters, EPCs, and active SDF-1α were determined.Results:After 4-month treatment with alogliptin, either Group A or Group B showed reduced HbA1c levels and concomitant similar increase in EPCs and active SDF-1α.Conclusions:Alogliptin showed significant benefits in increasing EPCs and active SDF-1α either in good or poor diabetes control. The study demonstrated that similar to other DPP-4-i, also alogliptin is able to increase EPC concentrations, suggesting the existence of a class effect mediated by SDF-1α. The extent of increase in EPCs is independent from baseline diabetes control.

Lercanidipine effect on circulating CD34+ progenitor cells in elderly patients: a randomized study

Objective: This randomized study evaluates the effects of lercanidipine – as well as its antihypertensive efficacy – on the number of circulating endothelial progenitor cells (EPCs) in elderly patients with hypertension.Research design and methods: In total, 61 patients with hypertension were randomly assigned to lercanidipine 10 mg/day or to other antihypertensive treatments (control group).Main outcome measures: Cytometry analysis was conducted at baseline, at 12 weeks and at 24 weeks. Routine clinical examination was also performed.Results: Overall, the number of circulating EPCs had already significantly increased with lercanidipine, compared with baseline values, after 12 weeks; this increase was sustained until the end of the study. On the other hand, the number of circulating EPCs remained stable in the control group throughout the study period. At 12 weeks, a significant reduction in blood pressure, compared with baseline values, was observed in both groups. Regression analysis showed a significant negative correlation between systolic blood pressure and the number of circulating EPCs.Conclusions: Although the limited number of patients and the short follow-up hamper the analysis, this study suggests that lercanidipine may increase EPC concentration independently from its anti-hypertensive effect.

Endothelial progenitor cells mobilisation after percutaneous coronary intervention: a pilot study

Background: The mobilisation process of endothelial progenitor cells (EPC) after stent implantation by percutaneous coronary intervention (PCI) is unclear because the circulating EPC levels are influenced by several pathophysiological factors. The objective was to analyse the kinetics of EPC concentration following elective PCI in patients with stable angina, and its relation with other biomarkers or parameters of cardiovascular function.Methods: Pilot study in stable angina patients (n = 30) for elective PCI and implantation of bare-metal stent (BMS), drug-eluting stent (DES) or EPC-capturing stent (ECS). Samples were taken at baseline, 6 h, 24 h and 6 months after PCI for biochemical analysis and EPC quantification by flow cytometry.Results: Baseline EPC levels, quantified in peripheral blood, were related with the extent of the coronary lesion and the percentage of stenosis. EPC concentration increased 6 hours after PCI in relation with plasma C-reactive protein concentration and returned to basal levels after 24 hours post-PCI.Conclusions: Baseline EPC levels are related with the extension of the lesion and stenosis whereas the kinetics of EPC mobilization showed to be related with C-reactive protein concentration. Endothelial activation seems to occur in response to EPC mobilization or vascular damage by PCI.

Circulating Endothelial Progenitor Cells in Youth: Fitness, Physical Activity and Adiposity.

Circulating endothelial progenitor cells (EPCs) are early markers of cardiovascular impairment. The role of EPCs in youth remains unclear, and is complicated by differences in how cells are identified. This study (1) described EPCs in pre- and late-pubertal males and females, (2) examined their association with fitness, activity and adiposity, and (3) compared EPCs to published cell definitions. 94 participants completed 2 sessions. During the first session, aerobic fitness (Wpeak) and moderate-to-vigorous physical activity (MVPA) were assessed. During the second session, percent body fat (%BF) was determined by DXA, and a fasted blood sample was collected to measure EPCs by flow cytometry. EPCs were identified as CD31(+)CD34(bright)CD45(dim)CD133(+). Samples were reanalyzed and cell counts were compared to 8 previously published EPC definitions. EPCs were similar in pre- and late-pubertal males and females (p>0.05). Neither EPC concentrations nor proportions were correlated with Wpeak (ρ=- 0.04 to-0.06), MVPA (ρ=- 0.09 to - 0.07) or %BF (ρ=0.20 to 0.14). Agreement between cell data analyzed according the different cell definitions ranged from Κ=-0.06 to 0.82. Our findings suggest that EPCs were not associated with fitness, MVPA or adiposity in youth. The overall poor agreement across definitions may be indicative of distinct EPC subpopulations.

Erythropoietin-enhanced endothelial progenitor cell recruitment in peripheral blood and renal vessels during experimental acute kidney injury in rats.

Beneficial effects of erythropoietin (EPO) have been reported in acute kidney injury (AKI) when administered prior to induction of AKI. We studied the effects of EPO administration on renal function shortly after ischemic AKI. For this purpose, rats were subjected to renal ischemia for 30 min and EPO was administered at a concentration of 500 U/kg either i.v. as a single shot directly after ischemia or with an additional i.p. dose until 3 days after surgery. The results were compared with AKI rats without EPO application and a sham-operated group. Renal function was assessed by measurement of serum biochemical markers, histological grading, and using an isolated perfused kidney (IPK) model. Furthermore, we performed flow cytometry to analyze the concentration of endothelial progenitor cells (EPCs) in the peripheral blood and renal vessels. Following EPO application, there was only a statistically non-significant tendency of serum creatinine and urea to improve, particularly after daily EPO application. Renal vascular resistance and the renal perfusion rate were not significantly altered. In the histological analysis, acute tubular necrosis was only marginally ameliorated following EPO administration. In summary, we could not demonstrate a significant improvement in renal function when EPO was applied after AKI. Interestingly, however, EPO treatment resulted in a highly significant increase in CD133- and CD34-positive EPC both in the peripheral blood and renal vessels.

Endothelial Progenitor Cells in Kidney Transplant Patients.

Background: Circulating bone-marrow derived endothelial progenitor cells (EPCs) promote vascular repair. Lower concentrations of EPCs correlate with cardiovascular risk. In uremic patients, the number of functionally active EPCs is reduced. Kidney transplantation (KTx) improves both survival and endothelial function in patients with advanced renal failure. The aim of this study was to determine the impact of KTx and immunosuppressive therapy on the number of EPCs. Methods: EPCs were measured by flow cytometry analysis in 51 renal transplant patients (52±13,92 years; mean eGFR 52,61±19,90 ml/min) and 25 healthy subjects (49±15 years; mean eGFR 94±23 ml/min). We examined the associations between counts of EPCs and traditional cardiovascular risk factors, uremia related risk factors, kidney function and immunosuppressive agents. Results: EPCs numbers were similar in Kidney transplant recipients and controls. We found significant (p<0.05) independent inverse associations between counts of EPCs and age, sistolic and diastolic blood pressure and C-Reactive Protein (CRP). Renal transplant recipients with reduced graft function (mean eGFR <30 ml/min) had lower EPCs counts compared with healthy volunteers(1,05-05 ± 1,17-05 vs.3,95-04 ± 8,35-04 as % on 5x106 PBMc; p=0,0105). Patients receiving regimen therapy including corticosteroids showed significantly lower EPCs number (1,77-02± 1,24-02 vs.6,74-04 ± 9,77-04 as % on 5x106 PBMc; p<0,0001). The use of Cyclosporine and Everolimus induced a further decrease in EPCs number compared to Cyclosporine and Mycophenolate (7,70-05 ± 1,65-04 vs.6,74-04 ± 9,77-04 as % on 5x106 PBMc; p=0,0044). Conclusions: EPCs numbers in KTx are comparable to those found in healthy subjects. In addition, this study suggests negative associations in KTx between EPC counts and age, blood pressure, CRP, graft function and use of some immunosuppressive drugs combination. These findings indicate an improved potential for endothelial repair after KTx, suggest a different effect from different anti-rejection drugs and emphasize the role of EPCs as marker of endothelial health and predictors of cardiovascular outcomes.

SAT0030 Circulating Endothelial Microparticles and Endothelial Progenitors Cells in Primary SjÖGren's Syndrome: New Markers of Chronic Endothelial Damage?

BackgroundSubclinical atherosclerosis can be considered a form of systemic involvement in patients with chronic inflammatory joint and connective tissue diseases. Multiple factors, including inflammatory and immune-mediated mechanisms, have been identified...

Resistance Exercise Increases Endothelial Progenitor Cells and Angiogenic Factors

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. The objective of this study is to determine the influence of a single bout of MERE on circulating EPC and related angiogenic factors. 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. 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. Short intense bouts of MERE can trigger increases in circulating EPC and related angiogenic factors, potentially contributing to vascular adaptation and vasculoprotection.

SAT0325 Fenofibrate effects on pain, function, cytokine production, and circulating endothelial progenitor cells in patients with erosive osteoarthritis

BackgroundAnti-inflammatory and antiatherogenic properties of peroxisome proliferator-activated α (PPARα) receptor agonists (fibrates) suggest their utility in the treatment of various inflammatory rheumatic disorders associated with accelerated atherosclerosis. They include osteoarthritis...

THU0142 Fenofibrate reduces inflammation but has no effect on endothelial progenitor cells in patients with rheumatoid arthritis

BackgroundExperimental findings indicate that peroxisome proliferator-activated α (PPARα) receptor agonists (fibrates), apart from their lipid-lowering effects, exhibit anti-inflammatory activity, influence angiogenesis and modulate glucocorticoid effects. Recent data suggest that fibrates...

Treatment of erosive osteoarthritis with peroxisome proliferator-activated receptor alpha agonist fenofibrate: a pilot study

Hand osteoarthritis (HOA) is a common condition associated with high disease burden and frequently accompanied by comorbidities including dyslipidemia, atherosclerosis and obesity. The most debilitating HOA phenotype is erosive HOA (EHOA), characterized by synovial inflammation, formation of erosions, and substantial decline in hand function. Currently, there is no proven symptomatic treatment for the EHOA. Due to their broad spectrum effects directed on lipid metabolism, inflammation and pain, the agonists of peroxisome proliferator-activated receptor alpha or fibrates are a candidate class of drugs for the treatment of EHOA. In this study, we assessed the influence of fenofibrate treatment on clinical efficacy parameters, in vivo cytokine and adipokine production and concentrations of endothelial progenitor cells (EPC) in patients with EHOA. Fourteen patients received treatment with 145mg of fenofibrate/day for 12weeks. Fenofibrate treatment was associated with significant decreases in pain score, tender joint count, duration of morning stiffness, disease activity score, Cochin index, and ESR. Eight (57.14%) patients developed Outcome Measures in Rheumatology Clinical Trials-Osteoarthritis Research Society response at the end of treatment. Paracetamol consumption did not change during the treatment course. There was a significant reduction in triglyceride levels. No changes were detected in serum pro-inflammatory cytokine and adipokine concentrations while circulating IL-10 levels significantly decreased. There were no differences in circulating EPC numbers before and after the treatment. Fenofibrate was well tolerated, no patient experienced disease flare during the treatment. In conclusion, in EHOA patients, fenofibrate is associated with pleiotropic effects on pain, inflammation, and lipid profile. Larger, controlled studies are needed to confirm these results.

Abstract 383: Investigation of endothelial progenitor cells as mediators of radiation resistance.

Abstract Background: Radiation therapy delivered to locally advanced cancers is likely to kill most, if not all, of the endothelial cells lining the walls of blood vessels within and immediately surrounding the tumor. For the tumor to recur following radiation therapy, new vasculature must form either through angiogenesis, the sprouting of vessels from existing vessels, or by vasculogenesis, the seeding of blood vessels from circulating endothelial progenitor cells (EPCs). Because radiation is sufficient to abrogate local angiogenesis, we hypothesize that EPCs and other proangiogenic cells are recruited to tumors after radiation therapy, resulting in the recovery of the vascular network, and eventually, in the regrowth of the tumor. Methods: Nude mouse tissues and human U251 glioma xenografts were harvested, homogenized, and evaluated by flow cytometry for the EPC markers: CD117+, Flk-1+, and CD45-. EPCs were sorted and grown as primary cultures and examined for mature endothelial function using immunofluorescence for CD31 and acLDL uptake. Additionally, cultured EPCs were tested for stem cell and endothelial characteristics using tube formation and colony-forming assays. Finally, tumors and normal tissues were collected at various time points after radiation therapy and evaluated for % EPC populations present. Results: The highest concentrations of EPCs were in adipose tissue (7%), lungs (0.5%), aorta (0.5%) and glioma xenografts (0.5%) with other tissues demonstrating minimal EPC populations. EPCs could be isolated and grown as primary cultures where they demonstrated expression of the endothelial marker CD31, had endothelial function by uptake of acLDL, were able to form capillary networks on matrigel, and formed cell clusters in a colony-forming assay. Time course evaluation of EPC populations in tumors and normal lung tissue did not show an increase in EPCs at any time point after 10 Gy; however, there was approximately a 2-fold increase in EPCs present in peripheral blood at 7 days after irradiation. Additionally, an increased population of CD11b+ cells was present within the tumor 2-3 weeks after radiation therapy. Conclusions: EPCs (CD117+/Flk-1+/CD45-) were present in a variety of normal murine tissues and U251 human Glioma xenografts. While EPC populations did not increase within tumors after radiation, there was a consistent elevation of EPCs in peripheral blood during the first week after treatment with radiation. Furthermore, we were able to demonstrate a late influx of potentially proangiogenic CD11b+ monocytes within irradiated tumors. We are currently examining whether the EPC populations in irradiated tumors were originally present prior to radiation or were replaced by the radiation-induced EPC populations found in the peripheral blood. Finally, we are examining whether EPCs directly promote tumor initiation, tumor growth, and post-irradiation tumor recovery. Citation Format: Jeffery S. Russell, J. Martin Brown. Investigation of endothelial progenitor cells as mediators of radiation resistance. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 383. doi:10.1158/1538-7445.AM2013-383

The Effects of Age, Disease State, and Granulocyte Colony-Stimulating Factor on Progenitor Cell Count and Function in Patients Undergoing Cell Therapy for Cardiac Disease

The potential of autologous bone marrow (BM)-derived progenitor/stem cell (BMSC) therapy for cardiac repair maybe limited by patient-related factors, such as age and the disease process itself. In this exploratory analysis, we assessed the impact of age, different disease states, and granulocyte colony-stimulating factor (G-CSF) therapy on progenitor cell concentration and function in patients recruited to our clinical trials of BMSC therapy for ischaemic heart failure (IHD), dilated cardiomyopathy (DCM), and acute myocardial infarction (AMI). The concentrations of CD34+ cells and endothelial progenitor cells (EPCs) were measured in the peripheral blood (PB) and BM of 201 patients. Additionally, cell mobilization following G-CSF and the functional capability of CD34+ cells (using a colony-forming unit assay) were assessed. We found that older age was associated with a lower PB CD34+ cell concentration in the whole study group as well as blunting the effect of G-CSF on BMSC mobilization in IHD patients. Nonischaemic heart failure (DCM) was associated with a significantly higher baseline PB CD34+ and EPC concentration compared to IHD. Following G-CSF treatment, the CD34+ cell concentration was greater in the BM compared to PB, however, the PB CD34+ cells appeared to have a greater and improved (compared to baseline) functional potential. Our results suggest treatment with G-CSF improves the functional potential of mobilized circulating progenitor cells compared to those in the BM. Further work is required to determine which source of cells is best for the purposes of cardiac repair following G-CSF therapy.