Abstract
Pulmonary arterial hypertension (PAH) is characterized by vascular remodeling associated with obliteration of pulmonary arterioles and formation of plexiform lesions composed of hyperproliferative endothelial and vascular smooth-muscle cells. Here we describe a microRNA (miRNA)-dependent association between apelin (APLN) and fibroblast growth factor 2 (FGF2) signaling in pulmonary artery endothelial cells (PAECs). APLN deficiency in these cells led to increased expression of FGF2 and its receptor FGFR1 as a consequence of decreased expression of miR-424 and miR-503, which directly target FGF2 and FGFR1. miR-424 and miR-503 were downregulated in PAH, exerted antiproliferative effects in PAECs and inhibited the capacity of PAEC-conditioned medium to induce the proliferation of pulmonary artery smooth-muscle cells. Reconstitution of miR-424 and miR-503 in vivo ameliorated pulmonary hypertension in experimental models. These studies identify an APLN-dependent miRNA-FGF signaling axis needed for the maintenance of pulmonary vascular homeostasis.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apelin
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Cell Movement
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Cell Proliferation
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Cells, Cultured
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Culture Media, Conditioned / pharmacology
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Down-Regulation
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Endothelial Cells / metabolism
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Familial Primary Pulmonary Hypertension
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Fibroblast Growth Factor 2 / biosynthesis
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Fibroblast Growth Factor 2 / metabolism*
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Humans
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Hypertension, Pulmonary / genetics
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Hypertension, Pulmonary / metabolism*
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Hypertension, Pulmonary / pathology
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Intercellular Signaling Peptides and Proteins / metabolism*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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MicroRNAs / genetics
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MicroRNAs / metabolism*
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Muscle, Smooth, Vascular / metabolism
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Muscle, Smooth, Vascular / physiology
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Myocytes, Smooth Muscle / metabolism
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Pulmonary Artery / metabolism
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Pulmonary Artery / pathology
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Pulmonary Artery / physiopathology
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RNA Interference
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RNA, Small Interfering
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Rats
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Receptor, Fibroblast Growth Factor, Type 1 / biosynthesis
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Signal Transduction
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Vascular Diseases / metabolism
Substances
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APLN protein, human
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Apelin
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Culture Media, Conditioned
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Intercellular Signaling Peptides and Proteins
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MIRN424 microrna, human
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MIRN503 microRNA, human
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MicroRNAs
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RNA, Small Interfering
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Fibroblast Growth Factor 2
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FGFR1 protein, human
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Receptor, Fibroblast Growth Factor, Type 1