{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T20:57:11Z","timestamp":1791320231452,"version":"4.3.1"},"reference-count":45,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2014,8,1]],"date-time":"2014-08-01T00:00:00Z","timestamp":1406851200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Rationale<\/jats:title>\n                    <jats:p>Pulmonary arterial hypertension (PAH) is characterized by significant exercise intolerance, which is multifactorial and involves skeletal muscle alterations. There is growing evidence that microRNAs (miRs) are involved in PAH pathogenesis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>We hypothesized that miR-126, an endothelial-specific, proangiogenic miR, is down-regulated in the peripheral muscles of patients with PAH, which would account for skeletal muscle microcirculation loss and exercise intolerance.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Measurements and Main Results<\/jats:title>\n                    <jats:p>Patients with PAH displayed decreases in exercise capacity (V. \u00a0o2max) and microcirculation loss on quadriceps muscle biopsy (in CD31+ immunofluorescence experiments) compared to control subjects. Exercise capacity correlated with muscle capillarity (r = 0.84, P &amp;lt; 0.01). At the cellular level, vascular endothelial growth factor (VEGF) and VEGF receptor 2 expression were similar in both groups. Conversely, PAH was associated with a 60% decrease in miR-126 expression in a quantitative reverse transcriptase polymerase chain reaction experiment (P &amp;lt; 0.01), resulting in up-regulation of its targeted protein, Sprouty-related, EVH1 domain\u2013containing protein 1 (SPRED-1), and a marked decrease in the downstream effectors of the VEGF pathway, p-Raf\/Raf and p-ERK\/ERK, as determined by immunoblot analysis. Using freshly isolated CD31+ cells from human quadriceps biopsies, we found that the down-regulation of miR-126 in PAH triggered the activation of SPRED-1, impairing the angiogenic response (Matrigel assay). These abnormalities were reversed by treating the PAH cells with miR-126 mimic, whereas inhibition of miR-126 (antagomir) in healthy CD31+ cells fully mimicked the PAH phenotype. Finally, miR-126 down-regulation in skeletal muscle of healthy rats decreased muscle capillarity in immunofluorescence assays (P &amp;lt; 0.05) and exercise tolerance in treadmill tests (P &amp;lt; 0.05), whereas miR-126 up-regulation increased them in monocrotaline PAH rats.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>We demonstrate for the first time that exercise intolerance in PAH is associated with skeletal muscle microcirculation loss and impaired angiogenesis secondary to miR-126 down-regulation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1164\/rccm.201402-0383oc","type":"journal-article","created":{"date-parts":[[2014,6,30]],"date-time":"2014-06-30T11:35:55Z","timestamp":1404128155000},"page":"318-328","source":"Crossref","is-referenced-by-count":123,"title":["Impaired Angiogenesis and Peripheral Muscle Microcirculation Loss Contribute to Exercise Intolerance in Pulmonary Arterial Hypertension"],"prefix":"10.1093","volume":"190","author":[{"given":"Fran\u00e7ois","family":"Potus","sequence":"first","affiliation":[{"name":"Pulmonary Hypertension Research Group, Quebec Heart and Lung Institute Research Center, Laval University, Quebec City, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Malenfant","sequence":"additional","affiliation":[{"name":"Pulmonary Hypertension Research Group, Quebec Heart and Lung Institute Research Center, Laval University, Quebec City, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin","family":"Graydon","sequence":"additional","affiliation":[{"name":"Pulmonary Hypertension Research Group, Quebec Heart and Lung Institute Research Center, Laval University, Quebec City, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"Mainguy","sequence":"additional","affiliation":[{"name":"Pulmonary Hypertension 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