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miR‐126 Dependent Decrease of Skeletal Muscle Microcirculation Contribute to Exercise Intolerance in Pulmonary Arterial Hypertension.
Author(s) -
Potus francois,
Malenfant simon,
BreuilsBonnet Sandra,
Margaillan guillaume,
Bonnet sébastien,
Provencher steeve
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.778.2
Subject(s) - downregulation and upregulation , exercise intolerance , cd31 , medicine , microcirculation , skeletal muscle , endocrinology , pulmonary hypertension , in vivo , vascular resistance , angiogenesis , cardiology , hemodynamics , heart failure , biology , biochemistry , microbiology and biotechnology , gene
Pulmonary arterial hypertension (PAH) is characterized by a significant exercise intolerance which does not correlates with the cardiac output at rest and during exercise. Interestingly a close relationship between muscle circulation, exercise capacity and miR‐126 (pro‐angiogenic miRNA) had been shown. We hypothesized that miR‐126 is downregulated in peripheral muscles of PAH patients, decreasing microcirculation and contributing to exercise intolerance. Compared to control patients matched by both age and sex, PAH patients displayed dramatic decrease in exercise tolerance. This decrease correlates with a diminution in quadriceps microcirculation (CD31 immunofluorescence) and associated with a significant downregulation of miR‐126 expression. In vitro, using isolated CD31+ cells from human quadriceps biopsies, we demonstrated that the downregulation of miR‐126 triggered the activation of SPRED‐1 in PAH impairing the angiogenic response. All these abnormalities were reversed by treating the cells with miR126 mimic; while inhibition of miR126 in healthy cells mimic the PAH phenotype. In vivo, intraquadriceps injection of miR‐126 antagomir significantly reduced exercise tolerance compared to rats control. 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.