TY - JOUR T1 - miR-126; link between angiogenesis and exercise intolerance in pulmonary arterial hypertension JF - European Respiratory Journal JO - Eur Respir J VL - 44 IS - Suppl 58 SP - P303 AU - Francois Potus AU - Simon Malenfant AU - Sandra Breuils-Bonnet AU - Sébastien Bonnet AU - Steeve Provencher Y1 - 2014/09/01 UR - http://erj.ersjournals.com/content/44/Suppl_58/P303.abstract N2 - INTRODUCTION: Pulmonary arterial hypertension (PAH) is characterized by a significant exercise intolerance which does not correlates with the cardiac output at rest and during exercise. Thus intrinsic skeletal muscle dysfunctions may contribute to exercise intolerance in PAH. Several studies have shown a close relationship between muscle circulation, exercise capacity and miR-126, an endothelial specific pro-angiogenic miRNA. We hypothesized that miR-126 is downregulated in peripheral muscles of PAH patients, decreasing microcirculation and contributing to exercise intolerance. METHODS/RESULTS: Compared to control patients matched by both age and sex, PAH patients displayed dramatic decrease in exercise tolerance. This decrease correlates with a significant diminution in quadriceps microcirculation measured by CD31 immunofluorescence. At the cellular level, the decrease in microcirculation was associated with a significant downregulation of miR-126 expression Interestingly microcirculation and miR-126 expression are also decreased in intercostal muscle of PAH patient compared to control. In vitro, using freshly isolated CD31+ cells from human quadriceps biopsies; we demonstrated that the downregulation of miR-126 triggered the activation of SPRED-1 leading to VEGF/ERK pathway effector downregulation in PAH impairing the angiogenic response. All these abnormalities were reversed by treating the cells with miR126 mimic; while inhibition of miR126 in healthy CD31+ cells fully mimic the PAH phenotype. CONCLUSION: We demonstrated for the first time that exercise intolerance in PAH is associated with the decrease of skeletal muscle angiogenesis secondary to the downregulation of miR-126. ER -