• Chronic obstructive pulmonary disease
• MAP2K4
• Pulmonary artery smooth muscle cell
• The PI3K/AKT pathway
• miR-627-5p

• hypertension, pulmonary
• hypoxia
• lung diseases, interstitial
• prevalence
• ventricular dysfunction, right

Endothelial dysfunction and destruction of the pulmonary microcirculation are important pathogenic factors in chronic obstructive pulmonary disease (COPD). In COPD, bronchial obstruction is associated with endothelial dysfunction. Thus, new pharmacological treatment options aimed at restoring the pulmonary endothelium represent a clinical need in COPD therapy. Notch1 has been shown to protect cells against apoptosis, inflammation, and oxidative stress caused by cigarette smoke extract (CSE). Therefore, drug which effect on Notch1 may be a potential therapeutic target for COPD in the future.

In this study, we assessed the potential of spiperone to mediate regeneration of pulmonary endothelium in model of pulmonary emphysema induced by a CSE and lipopolysaccharide (LPS) in female C57BL/6 mice.

Spiperone increased the number of capillaries as well as the expression of the CD31 in the alveolar tissue compared to the controls. Moreover, application of spiperone prevented alveolar wall destruction (DI), and reduced the area of emphysema. Lastly, we demonstrated that spiperone positively influenced mobilization and migration of endothelial progenitor cells (EPC, CD45⁻CD34⁺CD31⁺), CD309⁺-endothelial cells, and angiogenesis precursors (CD45⁻CD117⁺CD309⁺) into the lung. Spiperone administration significantly reduced the number Notch1 positive CD309⁺-endothelial cells and Notch1+ EPCs.

Overall, our results suggest that spiperone mediates endothelial regeneration in an animal model of COPD. Thus, it could represent a novel therapeutic approach for treatment of emphysema associated with COPD.

• Notch1
• VEGF2 (CD309)
• endothelial progenitor cells
• endothelial regeneration
• pulmonary emphysema
• spiperone

• CART therapy
• COPD
• cancer stem cell
• inflammation
• small cell lung cancer

• Cell Proliferation/genetics
• Cellular Senescence/genetics
• Endothelial Progenitor Cells/metabolism
• Humans
• Pulmonary Disease, Chronic Obstructive/genetics
• Pulmonary Disease, Chronic Obstructive/metabolism
• Sp1 Transcription Factor/genetics
• Sp1 Transcription Factor/metabolism
• Nicotiana

• emphysema
• imaging
• longitudinal
• lung function
• pulmonary circulation

• Disease Progression
• Endothelium, Vascular/diagnostic imaging
• Endothelium, Vascular/pathology
• Female
• Humans
• Longitudinal Studies
• Male
• Middle Aged
• Pulmonary Artery/diagnostic imaging
• Pulmonary Artery/pathology
• Pulmonary Disease, Chronic Obstructive/diagnostic imaging
• Pulmonary Disease, Chronic Obstructive/genetics
• Pulmonary Disease, Chronic Obstructive/physiopathology
• Respiratory Function Tests
• Smokers
• Tomography, X-Ray Computed

• R01 HL149877 NHLBI NIH HHS
• R01 HL133137 NHLBI NIH HHS
• K23 HL141651 NHLBI NIH HHS
• U01 HL089897 NHLBI NIH HHS
• R01 HL116931 NHLBI NIH HHS
• R01 HL116473 NHLBI NIH HHS
• U01 HL089856 NHLBI NIH HHS
• R01 HL149861 NHLBI NIH HHS
• R01 HL148215 NHLBI NIH HHS
• T32 HL105346 NHLBI NIH HHS

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide and encompasses chronic bronchitis and emphysema. It has been shown that vascular wall remodeling and pulmonary hypertension (PH) can occur not only in patients with COPD but also in smokers with normal lung function, suggesting a causal role for vascular alterations in the development of emphysema. Mechanistically, abnormalities in the vasculature, such as inflammation, endothelial dysfunction, imbalances in cellular apoptosis/proliferation, and increased oxidative/nitrosative stress promote development of PH, cor pulmonale, and most probably pulmonary emphysema. Hypoxemia in the pulmonary chamber modulates the activation of key transcription factors and signaling cascades, which propagates inflammation and infiltration of neutrophils, resulting in vascular remodeling. Endothelial progenitor cells have angiogenesis capabilities, resulting in transdifferentiation of the smooth muscle cells via aberrant activation of several cytokines, growth factors, and chemokines. The vascular endothelium influences the balance between vaso-constriction and -dilation in the heart. Targeting key players affecting the vasculature might help in the development of new treatment strategies for both PH and COPD. The present review aims to summarize current knowledge about vascular alterations and production of reactive oxygen species in COPD. The present review emphasizes on the importance of the vasculature for the usually parenchyma-focused view of the pathobiology of COPD.

• COPD
• emphysema
• hypoxia
• oxidative stress
• pulmonary hypertension

• Chronic obstructive pulmonary disease
• EPC
• Endothelial dysfunction
• Eosinophilic inflammation
• Supplemental oxygen

• Bronchiectasis
• Cardiovascular disease (CVD)
• Endothelial progenitor cells (EPCs)
• Systemic inflammation

• Aged
• Biomarkers/blood
• Bronchiectasis/blood
• Bronchiectasis/diagnosis
• Bronchiectasis/pathology
• Bronchiectasis/physiopathology
• Cell Movement
• Cell Proliferation
• Cells, Cultured
• Endothelial Progenitor Cells/pathology
• Female
• Forced Expiratory Volume
• Humans
• Inflammation
• Interleukin-6/blood
• Male
• Middle Aged
• Severity of Illness Index

• Notch1 signaling
• endothelial progenitor cells
• pulmonary emphysema
• spiperone
• α1-antitrypsin

• Animals
• Dopamine Antagonists/pharmacology
• Endothelial Progenitor Cells/drug effects
• Endothelial Progenitor Cells/metabolism
• Endothelial Progenitor Cells/pathology
• Female
• Galactosamine/administration & dosage
• Gene Expression Regulation
• Hepatocytes/drug effects
• Hepatocytes/metabolism
• Hepatocytes/pathology
• Liver/drug effects
• Liver/metabolism
• Liver/pathology
• Lung/drug effects
• Lung/metabolism
• Lung/pathology
• Mice
• Mice, Inbred C57BL
• Neovascularization, Physiologic/drug effects
• Pancreatic Elastase/administration & dosage
• Phosphorylation/drug effects
• Platelet Endothelial Cell Adhesion Molecule-1/genetics
• Platelet Endothelial Cell Adhesion Molecule-1/metabolism
• Pulmonary Emphysema/chemically induced
• Pulmonary Emphysema/drug therapy
• Pulmonary Emphysema/genetics
• Pulmonary Emphysema/metabolism
• Receptor, Notch1/agonists
• Receptor, Notch1/genetics
• Receptor, Notch1/metabolism
• Receptors, Dopamine D2/genetics
• Receptors, Dopamine D2/metabolism
• Regeneration/drug effects
• Spiperone/pharmacology
• Vascular Endothelial Growth Factor Receptor-2/genetics
• Vascular Endothelial Growth Factor Receptor-2/metabolism
• alpha 1-Antitrypsin/genetics
• alpha 1-Antitrypsin/metabolism
• alpha 1-Antitrypsin Deficiency/drug therapy
• alpha 1-Antitrypsin Deficiency/enzymology
• alpha 1-Antitrypsin Deficiency/genetics
• alpha 1-Antitrypsin Deficiency/pathology

Pulmonary vascular abnormalities are a characteristic feature of chronic obstructive pulmonary disease (COPD). Cigarette smoking is the most important risk factor for COPD. It is believed that its constant exposure triggers endothelial cell damage and vascular remodelling. Under pathological conditions, progenitor cells (PCs) are mobilized from the bone marrow and recruited to sites of vascular injury. The aim of the study was to investigate whether in COPD the number of circulating PCs is related to the presence of bone marrow-derived cells in pulmonary arteries and the association of these phenomena to both systemic and pulmonary endothelial dysfunction.

Thirty-nine subjects, 25 with COPD, undergoing pulmonary resection because of a localized carcinoma, were included. The number of circulating PCs was assessed by flow cytometry using a triple combination of antibodies against CD45, CD133 and CD34. Infiltrating CD45⁺ cells were identified by immunohistochemistry in pulmonary arteries. Endothelial function in systemic and pulmonary arteries was measured by flow-mediated dilation and adenosine diphosphate-induced vasodilation, respectively.

COPD patients had reduced numbers of circulating PCs (p < 0.05) and increased numbers of CD45⁺ cells (< 0.05) in the pulmonary arterial wall than non-COPD subjects, being both findings inversely correlated (r = − 0.35, p < 0.05). In pulmonary arteries, the number of CD45⁺ cells correlated with the severity of vascular remodelling (r = 0.4, p = 0.01) and the endothelium-dependent vasodilation (r = − 0.3, p = 0.05). Systemic endothelial function was unrelated to the number of circulating PCs and changes in pulmonary vessels.

In COPD, the decrease of circulating PCs is associated with their recruitment in pulmonary arteries, which in turn is associated with endothelial dysfunction and vessel remodelling, suggesting a mechanistic link between these phenomena. Our findings are consistent with the notion of an imbalance between endothelial damage and repair capacity in the pathogenesis of pulmonary vascular abnormalities in COPD.

The online version of this article (10.1186/s12931-019-1024-z) contains supplementary material, which is available to authorized users.

• COPD
• DLco
• Endothelial dysfunction
• Progenitor cells
• Vascular remodeling

• COPD
• microRNAs
• pulmonary artery
• smooth muscle cell phenotypic switch
• vascular remodeling

Circulating endothelial microparticles (EMPs) and progenitor cells (PCs) are biological markers of endothelial function and endogenous repair capacity. The study was aimed to investigate whether COPD patients have an imbalance between EMPs to PCs compared to controls and to evaluate the effect of cigarette smoke on these circulating markers.

Circulating EMPs and PCs were determined by flow cytometry in 27 nonsmokers, 20 smokers and 61 COPD patients with moderate to severe airflow obstruction. We compared total EMPs (CD31⁺CD42b^-), apoptotic if they co-expressed Annexin-V⁺ or activated if they co-expressed CD62E⁺, circulating PCs (CD34⁺CD133⁺CD45⁺) and the EMPs/PCs ratio between groups.

COPD patients presented increased levels of total and apoptotic circulating EMPs, and an increased EMPs/PCs ratio, compared with nonsmokers. Women had less circulating PCs than men through all groups and those with COPD showed lower levels of PCs than both control groups. In smokers, circulating EMPs and PCs did not differ from nonsmokers, being the EMPs/PCs ratio in an intermediate position between COPD and nonsmokers.

We conclude that COPD patients present an imbalance between endothelial damage and repair capacity that might explain the frequent concurrence of cardiovascular disorders. Factors related to the disease itself and gender, rather than cigarette smoking, may account for this imbalance.

• Aged
• Apoptosis
• Case-Control Studies
• Cell-Derived Microparticles/pathology
• Cell-Derived Microparticles/physiology
• Endothelial Progenitor Cells/pathology
• Endothelial Progenitor Cells/physiology
• Endothelium, Vascular/pathology
• Endothelium, Vascular/physiopathology
• Female
• Humans
• Male
• Middle Aged
• Pulmonary Disease, Chronic Obstructive/blood
• Pulmonary Disease, Chronic Obstructive/pathology
• Pulmonary Disease, Chronic Obstructive/physiopathology
• Regeneration/physiology
• Respiratory Function Tests
• Smoking/blood
• Smoking/pathology
• Smoking/physiopathology

• Instituto de Salud Carlos III

• MR flowing imaging
• lung function/COPD
• pulmonary artery
• strain

• Aged
• Atherosclerosis/diagnostic imaging
• Cohort Studies
• Cross-Sectional Studies
• Emphysema/diagnostic imaging
• Ethnicity
• Female
• Gases
• Heart/diagnostic imaging
• Humans
• Lung/diagnostic imaging
• Male
• Middle Aged
• Observer Variation
• Plethysmography
• Pulmonary Artery/diagnostic imaging
• Pulmonary Disease, Chronic Obstructive/diagnostic imaging
• Pulmonary Emphysema/diagnostic imaging
• Risk Factors
• Sensitivity and Specificity
• Spirometry
• Tomography, X-Ray Computed
• Vascular Stiffness

• N01HC95169 NHLBI NIH HHS
• R01 HL077612 NHLBI NIH HHS
• UL1 RR024156 NCRR NIH HHS
• R01 HL093081 NHLBI NIH HHS
• R01 HL075476 NHLBI NIH HHS
• P30 DK054759 NIDDK NIH HHS
• K24 HL103844 NHLBI NIH HHS
• P30 ES009089 NIEHS NIH HHS
• R01 HL112986 NHLBI NIH HHS
• P30 ES005605 NIEHS NIH HHS

• COPD
• Endothelial dysfunction
• platelet
• thrombotic risk

• Endothelial progenitor cells
• angiogenesis
• chronic obstructive pulmonary disease (COPD)

Endothelial injury is implicated in the pathogenesis of COPD and emphysema; however the role of endothelial progenitor cells (EPCs), a marker of endothelial cell repair, and circulating endothelial cells (CECs), a marker of endothelial cell injury, in COPD and its subphenotypes is unresolved. We hypothesized that endothelial progenitor cell populations would be decreased in COPD and emphysema and that circulating endothelial cells would be increased. Associations with other subphenotypes were examined. The Multi-Ethnic Study of Atherosclerosis COPD Study recruited smokers with COPD and controls age 50–79 years without clinical cardiovascular disease. Endothelial progenitor cell populations (CD34+KDR+ and CD34+KDR+CD133+ cells) and circulating endothelial cells (CD45dimCD31+CD146+CD133-) were measured by flow cytometry. COPD was defined by standard spirometric criteria. Emphysema was assessed qualitatively and quantitatively on CT. Full pulmonary function testing and expiratory CTs were measured in a subset. Among 257 participants, both endothelial progenitor cell populations, and particularly CD34+KDR+ endothelial progenitor cells, were reduced in COPD. The CD34+KDR+CD133+ endothelial progenitor cells were associated inversely with emphysema extent. Both endothelial progenitor cell populations were associated inversely with extent of panlobular emphysema and positively with diffusing capacity. Circulating endothelial cells were not significantly altered in COPD but were inversely associated with pulmonary microvascular blood flow on MRI. There was no consistent association of endothelial progenitor cells or circulating endothelial cells with measures of gas trapping. These data provide evidence that endothelial repair is impaired in COPD and suggest that this pathological process is specific to emphysema.

• Circulating progenitor cells
• PAH-targeted therapy
• Treatment-naïve patients

• COPD
• emphysema
• endothelial dysfunction
• pulmonary blood flow
• sildenafil

Chronic obstructive pulmonary disease (COPD) is characterized by fixed airflow limitation and progressive decline of lung function and punctuated by occasional exacerbations. The disease pathogenesis may involve activation of the bone marrow stimulating mobilization and lung-homing of progenitor cells. We investigated the hypothesis that lower circulating numbers of vascular endothelial progenitor cells (VEPCs) are a consequence of increased lung-sequestration in COPD. Nonatopic, current or ex-smokers with diagnosed COPD and nonatopic, nonsmoking normal controls were enrolled. Blood and induced sputum extracted primitive hemopoietic progenitors (HPCs) and VEPC were enumerated by flow cytometry. Migration and adhesive responses to fibronectin were assessed. In sputum, VEPC numbers were significantly greater in COPD compared to normal controls. In blood, VEPCs were significantly lower in COPD versus normal controls. There were no differences in HPC levels between the two groups in either compartment. Functionally, there was a greater migrational responsiveness of progenitors from COPD subjects to stromal cell-derived factor-1alpha (SDF-1α) compared to normal controls. This was associated with greater numbers of CXCR4⁺ progenitors in sputum from COPD. Increased migrational responsiveness of progenitor cells may promote lung-homing of VEPC in COPD which may disrupt maintenance and repair of the airways and contribute to COPD disease pathogenesis.

• Chronic obstructive pulmonary disease
• Idiopathic pulmonary fibrosis
• Pulmonary fibrosis
• Pulmonary hypertension
• Sarcoidosis

• hypoxia
• obstructive disease
• pulmonary circulation
• pulmonary remodelling
• targeted pulmonary arterial hypertension drugs

• COPD
• dual energy CT
• phenotypes
• pulmonary MRI
• pulmonary ventilation and perfusion
• quantitative CT

• Animals
• Clinical Trials as Topic
• Disease Progression
• Fluorine/chemistry
• Gadolinium/chemistry
• Helium/chemistry
• Humans
• Inflammation
• Isotopes/chemistry
• Lung/diagnostic imaging
• Magnetic Resonance Imaging
• Perfusion
• Phenotype
• Pulmonary Disease, Chronic Obstructive/diagnostic imaging
• Pulmonary Disease, Chronic Obstructive/physiopathology
• Reproducibility of Results
• Swine
• Tomography, X-Ray Computed
• Treatment Outcome
• Xenon Isotopes/chemistry

• R01 HL112986 NHLBI NIH HHS
• P30 ES005605 NIEHS NIH HHS
• R01 HL077612 NHLBI NIH HHS
• R01 HL126838 NHLBI NIH HHS
• R01 HL093081 NHLBI NIH HHS
• R01 HL121270 NHLBI NIH HHS
• P30 DK054759 NIDDK NIH HHS

• COPD
• angiopoietin
• gene expression profile
• pulmonary artery
• vascular remodeling

Elastase released from neutrophils as part of the innate immune system has been implicated in chronic diseases such as emphysema and cardiovascular disease. We have previously shown that neutrophil elastase targets vascular endothelial growth factor-A (VEGF) for partial degradation to generate a fragment of VEGF (VEGFf) that has distinct activities. Namely, VEGFf binds to VEGF receptor 1 but not to VEGF receptor 2 and shows altered signaling compared to intact VEGF. In the present study we investigated the chemotactic function of VEGF and VEGFf released from cells by neutrophil elastase. We found that endothelial cells migrated in response to intact VEGF but not VEGFf whereas RAW 264.7 macrophages/monocytes and embryonic endothelial progenitor cells were stimulated to migrate by either VEGF or VEGFf. To investigate the role of elastase-mediated release of VEGF from cells/extracellular matrices, a co-culture system was established. High or low VEGF producing cells were co-cultured with macrophages, endothelial or endothelial progenitor cells and treated with neutrophil elastase. Elastase treatment stimulated macrophage and endothelial progenitor cell migration with the response being greater with the high VEGF expressing cells. However, elastase treatment led to decreased endothelial cell migration due to VEGF cleavage to VEGF fragment. These findings suggest that the tissue response to NE-mediated injury might involve the generation of diffusible VEGF fragments that stimulate inflammatory cell recruitment.

• Animals
• Cattle
• Cell Movement
• Endothelial Progenitor Cells/drug effects
• Endothelial Progenitor Cells/physiology
• Humans
• Macrophages/drug effects
• Macrophages/physiology
• Mice
• Pancreatic Elastase/pharmacology
• Peptide Fragments/chemistry
• Peptide Fragments/pharmacology
• Proteolysis
• Rats
• Recombinant Proteins/chemistry
• Recombinant Proteins/pharmacology
• Sf9 Cells
• Spodoptera
• Vascular Endothelial Growth Factor A/chemistry
• Vascular Endothelial Growth Factor A/pharmacology

• HL088672 NHLBI NIH HHS

Long-term chronic intermittent exposure to altitude hypoxia is a labor phenomenon requiring further research. Using a rat model, we examined whether this type of exposure differed from chronic exposure in terms of pulmonary artery remodeling and other features. Rats were subjected to chronic hypoxia (CH, n = 9) and long-term intermittent hypoxia (CIH2x2; 2 days of hypoxia/2 days of normoxia, n = 10) in a chamber (428 Torr, 4,600 m of altitude) for 46 days and compared to rats under normoxia (NX, n = 10). Body weight, hematocrit, and right ventricle ratio were measured. Pulmonary artery remodeling was assessed using confocal microscopy of tissues stained with a nuclear dye (DAPI) and CD11b antibody. Both hypoxic conditions exhibited increased hematocrit and hypertrophy of the right ventricle, tunica adventitia, and tunica media, with no changes in lumen size. The medial hypertrophy area (larger in CH) depicted a significant increase in smooth muscle cell number. Additionally, CIH2x2 increased the adventitial hypertrophy area, with an increased cellularity and a larger prevalence of clustered inflammatory cells. In conclusion, CIH2x2 elicits milder effects on pulmonary artery medial layer muscularization and subsequent right ventricular hypertrophy than CH. However, CIH2x2 induces greater and characteristic alterations of the adventitial layer.

In chronic obstructive pulmonary disease (COPD), decreased progenitor cells and impairment of systemic vascular function have been suggested to confer higher cardiovascular risk. The origin of these changes and their relationship with alterations in the pulmonary circulation are unknown.

To investigate whether changes in the number of circulating hematopoietic progenitor cells are associated with pulmonary hypertension or changes in endothelial function.

62 COPD patients and 35 controls (18 non-smokers and 17 smokers) without cardiovascular risk factors other than cigarette smoking were studied. The number of circulating progenitors was measured as CD45⁺CD34⁺CD133⁺ labeled cells by flow cytometry. Endothelial function was assessed by flow-mediated dilation. Markers of inflammation and angiogenesis were also measured in all subjects.

Compared with controls, the number of circulating progenitor cells was reduced in COPD patients. Progenitor cells did not differ between control smokers and non-smokers. COPD patients with pulmonary hypertension showed greater number of progenitor cells than those without pulmonary hypertension. Systemic endothelial function was worse in both control smokers and COPD patients. Interleukin-6, fibrinogen, high sensitivity C-reactive protein, vascular endothelial growth factor and tumor necrosis factor were increased in COPD. In COPD patients, the number of circulating progenitor cells was inversely related to the flow-mediated dilation of systemic arteries.

Pulmonary and systemic vascular impairment in COPD is associated with cigarette smoking but not with the reduced number of circulating hematopoietic progenitors. The latter appears to be a consequence of the disease itself not related to smoking habit.

• AC133 Antigen
• Aged
• Antigens, CD/metabolism
• Antigens, CD34/metabolism
• Endothelium, Vascular/metabolism
• Endothelium, Vascular/physiopathology
• Female
• Glycoproteins/metabolism
• Hematopoietic Stem Cells/metabolism
• Hematopoietic Stem Cells/pathology
• Humans
• Hypertension, Pulmonary/metabolism
• Hypertension, Pulmonary/pathology
• Hypertension, Pulmonary/physiopathology
• Leukocyte Common Antigens/metabolism
• Male
• Middle Aged
• Neovascularization, Pathologic/metabolism
• Neovascularization, Pathologic/pathology
• Neovascularization, Pathologic/physiopathology
• Peptides/metabolism
• Pulmonary Disease, Chronic Obstructive/metabolism
• Pulmonary Disease, Chronic Obstructive/pathology
• Pulmonary Disease, Chronic Obstructive/physiopathology
• Smoking

• Acute exacerbation
• CD34+ cells
• CRP
• Cardiac dysfunction
• Chronic Obstructive Pulmonary Disease (COPD)

Cigarette smoke is a major public health problem associated with multitude of diseases, including pulmonary and vascular diseases. Endothelial progenitor cells (EPCs) contribute to neovascularization and play an important role in the development of these diseases. The effect of CSE on EPCs is seldom studied. The aim of the current study is to observe the effect of CSE on biological behavior of EPCs and, further, to search for potential candidate agent in protection of proliferation of EPCs against the damage caused by CSE exposure in vitro. Methods. The proliferations of EPCs isolated from bone marrow of C57BL/6J mice were assessed by MTT after incubating the EPCs with a series of concentrations of CSE (1.0%, 2.5%, 5.0%, and 10.0%) for different times (3, 6, and 24 hours) as well as with 1.0% CSE in presence of 5-AZA-CdR for 24 hours. Results. The proliferations of EPCs were significantly enhanced after 3 hours of exposure to concentrations of 1.0% and 2.5% CSE but depressed when exposed to concentrations of 5.0% and 10.0% CSE. Furthermore, the 5-AZA-CdR in concentrations of 2.0 μmol/L and 5.0 μmol/L partly protected against the depression of proliferation of EPCs caused by CSE exposure. Conclusions. The CSE showed dual effects on proliferation of EPCs isolated from mice. The 5-AZA-CdR partly protected the proliferation of EPCs against the damage caused by CSE exposure in vitro, suggesting that DNA methylation may be involved in the dysfunction of EPCs induced by CSE.

Endothelial progenitor cells (EPCs) are capable of proliferating and differentiating into mature endothelial cells, and they have been considered as potential candidates for coronary heart disease therapy. However, the transition of EPCs to mesenchymal cells is not fully understood. This study aimed to explore the role of microRNA 126 (miR-126) in the endothelial-to-mesenchymal transition (EndMT) induced by transforming growth factor beta 1 (TGFβ1).

EndMT of rat bone marrow-derived EPCs was induced by TGFβ1 (5 ng/mL) for 7 days. miR-126 expression was depressed in the process of EPC EndMT. The luciferase reporter assay showed that the PI3K regulatory subunit p85 beta (PIK3R2) was a direct target of miR-126 in EPCs. Overexpression of miR-126 by a lentiviral vector (lenti-miR-126) was found to downregulate the mRNA expression of mesenchymal cell markers (α-SMA, sm22-a, and myocardin) and to maintain the mRNA expression of progenitor cell markers (CD34, CD133). In the cellular process of EndMT, there was an increase in the protein expression of PIK3R2 and the nuclear transcription factors FoxO3 and Smad4; PI3K and phosphor-Akt expression decreased, a change that was reversed markedly by overexpression of miR-126. Furthermore, knockdown of PIK3R2 gene expression level showed reversed morphological changes of the EPCs treated with TGFβ1, thereby giving the evidence that PIK3R2 is the target gene of miR-126 during EndMT process.

These results show that miR-126 targets PIK3R2 to inhibit EPC EndMT and that this process involves regulation of the PI3K/Akt signalling pathway. miR-126 has the potential to be used as a biomarker for the early diagnosis of intimal hyperplasia in cardiovascular disease and can even be a therapeutic tool for treating cardiovascular diseases mediated by the EndMT process.

• Animals
• Antigens, Differentiation/metabolism
• Cell Differentiation/physiology
• Endothelial Cells/cytology
• Endothelial Cells/metabolism
• Gene Expression Regulation, Enzymologic/physiology
• Male
• MicroRNAs/metabolism
• Phosphatidylinositol 3-Kinases/metabolism
• Proto-Oncogene Proteins c-akt/biosynthesis
• Rats
• Rats, Sprague-Dawley
• Signal Transduction/physiology
• Stem Cells/cytology
• Stem Cells/metabolism
• Transforming Growth Factor beta1/metabolism

• angiogenesis
• emphysema
• endothelial progenitor cell

Pulmonary hypertension is a prevalent complication of chronic obstructive pulmonary disease (COPD) that is associated with poor prognosis. Although pulmonary hypertension is usually diagnosed in patients with advanced disease, changes in pulmonary vessels are already apparent at early disease stages, and in smokers without airflow obstruction. Changes in pulmonary vessels include intimal hyperplasia, resulting from proliferating mesenchymal cells, and elastic and collagen deposition as well as endothelial dysfunction. Dysregulation of endothelium-derived mediators and growth factors and inflammatory mechanisms underlie the endothelial dysfunction and vessel remodeling. Circumstantial and experimental evidence suggests that cigarette smoke products can initiate pulmonary vascular changes in COPD and that, at advanced disease stages, hypoxia may amplify the effects of cigarette smoke on pulmonary arteries. Bone marrow-derived progenitor cells may contribute to vessel repair and to vessel remodeling, a process that appears to be facilitated by transforming growth factor-β.

• cigarette smoke
• endothelium
• progenitor cells
• vascular remodeling

• Cardiovascular disease
• Circulating endothelial cells
• Circulating progenitor cells
• Exercise

Endothelial dysfunction plays an important role in the pathogenesis of pulmonary arterial hypertension (PAH) in sickle cell disease (SCD). A variety of evidence suggests that circulating endothelial progenitor cells (EPCs) play an integral role in vascular repair. We hypothesized that SCD patients with PAH are deficient in EPCs, potentially contributing to endothelial dysfunction and disease progression. The number of circulating CD34+/CD14−/CD106+ EPCs was significantly lower in SCD patients with PAH than without PAH (P=0.025). CD34+/CD14−/CD106+ numbers significantly correlated with tricuspid regurgitation velocity (TRV, r=−0.44, P=0.033) 6-minute walk distance (6MWD, r= 0.72, P=0.001), mean pulmonary artery pressure (mPAP, r= −0.43, P=0.05), and pulmonary vascular resistance (PVR, r=−0.45, P=0.05). Other EPC subsets including CD31+/CD133+/CD146+ were similar between both groups. Numbers of EPCs did not correlate with age, sex, hemoglobin, WBC count, reticulocyte count, lactate dehydrogenase (LDH), iron/ferritin levels, and serum creatinine. These data indicate that subsets of EPC are lower in SCD patients with PAH than in those without PAH. Fewer EPCs in PAH patients may contribute to the pulmonary vascular pathology. Reduced number of EPCs in SCD patients with PAH might not only give potential insight into the pathophysiological mechanisms but also might be useful for identifying suitable therapeutic targets in these patients.

• associated pulmonary arterial hypertension
• pathogenic mechanism
• sickle cell disease
• stem cell

• angiotensin ii
• extracellular matrix remodeling
• hypertension
• intima
• nadph oxidase
• oxidative stress
• type 2 diabetes mellitus

• R01 HL073101 NHLBI NIH HHS

• Aged
• Animals
• Case-Control Studies
• Cell Adhesion
• Cell Proliferation
• Cell Separation/methods
• Cells, Cultured
• Centrifugation, Density Gradient
• Chemotaxis
• China
• Colony-Forming Units Assay
• Disease Models, Animal
• Endothelial Cells/metabolism
• Endothelial Cells/pathology
• Endothelial Cells/transplantation
• Femoral Artery/injuries
• Femoral Artery/pathology
• Flow Cytometry
• Human Umbilical Vein Endothelial Cells/metabolism
• Humans
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Middle Aged
• Neovascularization, Physiologic
• Platelet Endothelial Cell Adhesion Molecule-1/metabolism
• Pulmonary Disease, Chronic Obstructive/metabolism
• Pulmonary Disease, Chronic Obstructive/pathology
• Receptors, CXCR4/metabolism
• Stem Cell Transplantation
• Stem Cells/metabolism
• Stem Cells/pathology
• Time Factors
• Vascular Endothelial Growth Factor Receptor-2/metabolism
• Vascular System Injuries/pathology
• Vascular System Injuries/surgery

• Animals
• Anti-Inflammatory Agents/therapeutic use
• Biomarkers/analysis
• Chemistry, Pharmaceutical
• Humans
• Molecular Targeted Therapy
• Pulmonary Disease, Chronic Obstructive/diagnosis
• Pulmonary Disease, Chronic Obstructive/drug therapy
• Pulmonary Disease, Chronic Obstructive/physiopathology

• Fibrocyte
• angiogenesis
• inflammation
• pericyte