Inhibition of apelin expression by BMP signaling in endothelial cells.
The transforming growth factor-β/bone morphogenic protein (BMP) system is a major pathway for angiogenesis and is involved in hereditary vascular diseases. Here we report that the gene encoding the vasoactive and vascular cell growth-regulating peptide apelin is a target of the BMP pathway. We demonstrate that apelin expression is strongly downregulated by BMP in an endothelial cell line as well as in lung endothelial microvascular cells. We show that BMP signals through the BMPR2-SMAD pathway to downregulate apelin expression and that a transcriptional direct and indirect mechanism is required. The BMP-induced downregulation of apelin expression was found to be critical for hypoxia-induced growth of endothelial cells, because the growth inhibitory effect of BMP in this condition is suppressed by enforced expression of apelin. Thus, we describe an important link between a signaling pathway involved in angiogenesis and vascular diseases and a peptide regulating vascular homeostasis.
UMR_S 956 INSERM, 91 bvd de l'hôpital, F-75634 Paris cedex 13, France.
Odette
O
Poirier
Mariana
M
Ciumas
Mélanie
M
Eyries
Kevin
K
Montagne
Sophie
S
Nadaud
Florent
F
Soubrier
D000073861:Apelin; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism / Q000494:pharmacology; D055419:Bone Morphogenetic Protein 7 / Q000378:metabolism / Q000494:pharmacology; D019485:Bone Morphogenetic Proteins / Q000378:metabolism* / Q000494:pharmacology; D002460:Cell Line; D042783:Endothelial Cells / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D055427:Growth Differentiation Factor 2; D055412:Growth Differentiation Factors / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis* / Q000235:genetics; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D055806:Microvessels / Q000187:drug effects / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000139:chemically induced / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology* / Q000528:radiation effects*; D051785:Smad Proteins / Q000378:metabolism
C115436:APLN protein, human; D000073861:Apelin; C525809:BMP4 protein, human; C525819:BMP7 protein, human; D055415:Bone Morphogenetic Protein 4; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; C525887:GDF2 protein, human; D055427:Growth Differentiation Factor 2; D055412:Growth Differentiation Factors; D036341:Intercellular Signaling Peptides and Proteins; D051785:Smad Proteins