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Cilostazol Enhances Mobilization of Circulating Endothelial Progenitor Cells and Improves Endothelium-Dependent Function in Patients at High Risk of Cardiovascular Disease.
Chao, TH, Chen, IC, Lee, CH, Chen, JY, Tsai, WC, Li, YH, Tseng, SY, Tsai, LM, Tseng, WK
Angiology. 2016;(7):638-46
Abstract
This is the first study to investigate the vasculoangiogenic effects of cilostazol on endothelial progenitor cells (EPCs) and flow-mediated dilatation (FMD) in patients at high risk of cardiovascular disease (CVD). This double-blind, placebo-controlled study included 71 patients (37 received 200 mg/d cilostazol and 34 received placebo for 12 weeks). Use of cilostazol, but not placebo, significantly increased circulating EPC (kinase insert domain receptor(+)CD34(+)) counts (percentage changes: 149.0% [67.9%-497.8%] vs 71.9% [-31.8% to 236.5%], P = .024) and improved triglyceride and high-density lipoprotein cholesterol levels (P = .002 and P = .003, respectively). Plasma levels of vascular endothelial growth factor (VEGF)-A165 and FMD significantly increased (72.5% [32.9%-120.4%] vs -5.8% [-46.0% to 57.6%], P = .001; 232.8% ± 83.1% vs -46.9% ± 21.5%, P = .003, respectively) in cilostazol-treated patients. Changes in the plasma triglyceride levels significantly inversely correlated with the changes in the VEGF-A165 levels and FMD. Cilostazol significantly enhanced the mobilization of EPCs and improved endothelium-dependent function by modifying some metabolic and angiogenic markers in patients at high risk of CVD.
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Histological evaluation at different times after augmentation of extraction sites grafted with a magnesium-enriched hydroxyapatite: double-blinded randomized controlled trial.
Canullo, L, Heinemann, F, Gedrange, T, Biffar, R, Kunert-Keil, C
Clinical oral implants research. 2013;(4):398-406
Abstract
OBJECTIVES To histologically analyze the early angiogenesis-osteogenesis interplay in post-extraction sockets augmented with magnesium-enriched hydroxyapatite (Mg-enriched HA). MATERIAL AND METHODS Ten post-extraction sites underwent post-extraction ridge preservation procedure. According to randomization, sites were divided into two balanced groups and bone specimens were collected 2 or 4 months after surgery. Sections were stained with hematoxylin/eosin, Masson-Goldner trichrome, and tartrate-resistant acid phosphatase (TRAP), respectively. Furthermore, indirect immunohistochemistry was performed using alkaline phosphatase, CD34 and caveolin-1 antibodies. Mean values and standard deviations were calculated for each outcome variable. Data were then compared using one-way ANOVA test. P < 0.05 was considered statistically significant. RESULTS Histomorphometric analysis presented 15.0% (±3.5) regenerated bone after 2 months of healing. After 4 months, regenerated bone increased 5.1-fold up to 77.4% (± 8.6) (P < 0.001). On the contrary, vessels and capillary reduced from 645 (±33) to 255 (± 94) (caveolin-1 expression, P = 0.008). These findings were confirmed by CD34 expression (301 ± 95 and 88 (±24), respectively, at 2 and 4 months (P = 0.046). CONCLUSIONS Within the limits of the present randomized controlled study, it can be concluded that Mg-enriched HA is a suitable material for socket preservation and ensures early angiogenesis and early osteogenesis.
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Angiogenic response to passive movement and active exercise in individuals with peripheral arterial disease.
Hoier, B, Walker, M, Passos, M, Walker, PJ, Green, A, Bangsbo, J, Askew, CD, Hellsten, Y
Journal of applied physiology (Bethesda, Md. : 1985). 2013;(12):1777-87
Abstract
Peripheral arterial disease (PAD) is caused by atherosclerosis and is associated with microcirculatory impairments in skeletal muscle. The present study evaluated the angiogenic response to exercise and passive movement in skeletal muscle of PAD patients compared with healthy control subjects. Twenty-one PAD patients and 17 aged control subjects were randomly assigned to either a passive movement or an active exercise study. Interstitial fluid microdialysate and tissue samples were obtained from the thigh skeletal muscle. Muscle dialysate vascular endothelial growth factor (VEGF) levels were modestly increased in response to either passive movement or active exercise in both subject groups. The basal muscle dialysate level of the angiostatic factor thrombospondin-1 protein was markedly higher (P < 0.05) in PAD patients compared with the control subjects, whereas soluble VEGF receptor-1 dialysate levels were similar in the two groups. The basal VEGF protein content in the muscle tissue samples was ∼27% lower (P < 0.05) in the PAD patients compared with the control subjects. Analysis of mRNA expression for a range of angiogenic and angiostatic factors revealed a modest change with active exercise and passive movement in both groups, except for an increase (P < 0.05) in the ratio of angiopoietin-2 to angiopoietin-1 mRNA in the PAD group with both interventions. PAD patients and aged individuals showed a similar limited angiogenic response to active exercise and passive movement. The limited increase in muscle extracellular VEGF combined with an elevated basal level of thrombospondin-1 in muscle extracellular fluid of PAD patients may restrict capillary growth in these patients.
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Low-dose versus moderate-dose atorvastatin after acute myocardial infarction: 8-month effects on coronary flow reserve and angiogenic cell mobilisation.
Hong, SJ, Choi, SC, Kim, JS, Shim, WJ, Park, SM, Ahn, CM, Park, JH, Kim, YH, Lim, DS
Heart (British Cardiac Society). 2010;(10):756-64
Abstract
OBJECTIVE To compare the effects of atorvastatin 10 mg versus 40 mg in circulating angiogenic cell mobilisations and in restoring coronary flow reserve (CFR) during the 8-month follow-up in patients with a first acute myocardial infarction (AMI). DESIGN CFR was measured using an intracoronary Doppler wire in 102 patients with AMI at baseline and at 8 months. Changes in the absolute number of circulating angiogenic cells were measured at baseline, 1 day, 5 days and at 8 months. Stented patients were randomly assigned to either low-dose atorvastatin 10 mg (ATOR10, n=52) or moderate-dose atorvastatin 40 mg (ATOR40, n=50). Setting University Hospital. RESULTS CFR increased significantly in both groups during the 8-month follow-up. The 8-month increases from baseline in CFR were significantly greater in the ATOR40 group than in the ATOR10 group (0.99+/-0.69 vs 0.55+/-0.47, p=0.017, respectively). The serial increases in the absolute number of CD34+ and CXCR4+ cells were significantly greater in the ATOR40 group, especially at 24 h after the procedure (two-way repeated-measures analysis of variance: p=0.046 and p=0.022, respectively). Decreases from baseline for interleukin 6 (-2.94+/-3.31 vs -1.52+/-2.82 pg/ml), tumour necrosis factor alpha (-1.31+/-2.96 vs -0.01+/-1.29 pg/ml), soluble intercellular adhesion molecule-1 (-71+/-95 vs 37+/-83 ng/ml) and soluble vascular cell adhesion molecule-1 (-51+/-364 vs 190+/-204 ng/ml) were significantly greater in the ATOR40 group. CONCLUSIONS The recovery of microvascular integrity after acute ischaemic injury in the ATOR40 group was expedited by greater circulating angiogenic cell mobilisations such as CD34+ and CXCR4+ cells, together with greater decreases in inflammatory cytokines and low-density lipoprotein-cholesterol concentrations. Registration number http://ClinicalTrials.gov number, NCT00536887.
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alpha-Lipoic acid modulates extracellular matrix and angiogenesis gene expression in non-healing wounds treated with hyperbaric oxygen therapy.
Alleva, R, Tomasetti, M, Sartini, D, Emanuelli, M, Nasole, E, Di Donato, F, Borghi, B, Santarelli, L, Neuzil, J
Molecular medicine (Cambridge, Mass.). 2008;(3-4):175-83
Abstract
alpha-Lipoic acid (LA) has been found previously to accelerate wound repair in patients affected by chronic wounds who underwent hyperbaric oxygen (HBO) therapy. Because proteinases are important in wound repair, we hypothesized that LA may regulate matrix metalloproteinase (MMP) expression in cells that are involved in wound repair. Patients undergoing HBO therapy were double-blind randomized into two groups: the LA group and the placebo group. Gene expression profiles for MMPs and for angiogenesis mediators were evaluated in biopsies collected at the first HBO session, at the seventh HBO session, and after 14 days of HBO treatment. ELISA tests were used to validate microarray expression of selected genes. LA supplementation in combination with HBO therapy downregulated the inflammatory cytokines and the growth factors which, in turn, affect MMPs expression. The disruption of the positive autocrine feedback loops that maintain the chronic wound state promotes progression of the healing process.
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Regional angiogenesis with vascular endothelial growth factor in peripheral arterial disease: a phase II randomized, double-blind, controlled study of adenoviral delivery of vascular endothelial growth factor 121 in patients with disabling intermittent claudication.
Rajagopalan, S, Mohler, ER, Lederman, RJ, Mendelsohn, FO, Saucedo, JF, Goldman, CK, Blebea, J, Macko, J, Kessler, PD, Rasmussen, HS, et al
Circulation. 2003;(16):1933-8
Abstract
BACKGROUND "Therapeutic angiogenesis" seeks to improve perfusion by the growth of new blood vessels. The Regional Angiogenesis with Vascular Endothelial growth factor (RAVE) trial is the first major randomized study of adenoviral vascular endothelial growth factor (VEGF) gene transfer for the treatment of peripheral artery disease (PAD). METHODS AND RESULTS This phase 2, double-blind, placebo-controlled study was designed to test the efficacy and safety of intramuscular delivery of AdVEGF121, a replication-deficient adenovirus encoding the 121-amino-acid isoform of vascular endothelial growth factor, to the lower extremities of subjects with unilateral PAD. In all, 105 subjects with unilateral exercise-limiting intermittent claudication during 2 qualifying treadmill tests, with peak walking time (PWT) between 1 to 10 minutes, were stratified on the basis of diabetic status and randomized to low-dose (4x10(9) PU) AdVEGF121, high-dose (4x10(10) PU) AdVEGF121, or placebo, administered as 20 intramuscular injections to the index leg in a single session. The primary efficacy end point, change in PWT (DeltaPWT) at 12 weeks, did not differ between the placebo (1.8+/-3.2 minutes), low-dose (1.6+/-1.9 minutes), and high-dose (1.5+/-3.1 minutes) groups. Secondary measures, including DeltaPWT, ankle-brachial index, claudication onset time, and quality-of-life measures (SF-36 and Walking Impairment Questionnaire), were also similar among groups at 12 and 26 weeks. AdVEGF121 administration was associated with increased peripheral edema. CONCLUSIONS A single unilateral intramuscular administration of AdVEGF121 was not associated with improved exercise performance or quality of life in this study. This study does not support local delivery of single-dose VEGF121 as a treatment strategy in patients with unilateral PAD.