title: BMPER is an endothelial cell regulator and controls bone morphogenetic protein-4-dependent angiogenesis.
abstract: Bone morphogenetic proteins (BMPs) are involved in embryonic and adult blood vessel formation in health and disease. BMPER (BMP endothelial cell precursor-derived regulator) is a differentially expressed protein in embryonic endothelial precursor cells. In earlier work, we found that BMPER interacts with BMPs and when overexpressed antagonizes their function in embryonic axis formation. In contrast, in a BMPER-deficient zebrafish model, BMPER behaves as a BMP agonist. Furthermore, lack of BMPER induces a vascular phenotype in zebrafish that is driven by disarray of the intersomitic vasculature. Here, we investigate the impact of BMPER on endothelial cell function and signaling and elucidate its role in BMP-4 function in gain- and loss-of-function models. As shown by Western blotting and immunocytochemistry, BMPER is an extracellular matrix protein expressed by endothelial cells in skin, heart, and lung. We show that BMPER is a downstream target of FoxO3a and consistently exerts activating effects on endothelial cell sprouting and migration in vitro and in vivo. Accordingly, when BMPER is depleted from endothelial cells, sprouting is impaired. In terms of BMPER related intracellular signaling, we show that BMPER is permissive and necessary for Smad 1/5 phosphorylation and induces Erk1/2 activation. Most interestingly, BMPER is necessary for BMP-4 to exert its activating role in endothelial function and to induce Smad 1/5 activation. Vice versa, BMP-4 is necessary for BMPER activity. Taken together, BMPER is a dose-dependent endothelial cell activator that plays a unique and pivotal role in fine-tuning BMP activity in angiogenesis.
authors.affiliation: Department of Cardiology, University of Freiburg, Germany.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Heinke
authors.forename: Leonie
authors.initials: L
authors.lastname: Wehofsits
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhou
authors.forename: Christoph
authors.initials: C
authors.lastname: Zoeller
authors.forename: Kim-Miriam
authors.initials: KM
authors.lastname: Baar
authors.forename: Thomas
authors.initials: T
authors.lastname: Helbing
authors.forename: Anna
authors.initials: A
authors.lastname: Laib
authors.forename: Hellmut
authors.initials: H
authors.lastname: Augustin
authors.forename: Christoph
authors.initials: C
authors.lastname: Bode
authors.forename: Cam
authors.initials: C
authors.lastname: Patterson
authors.forename: Martin
authors.initials: M
authors.lastname: Moser
mesh_terms: D000818:Animals; D017209:Apoptosis; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D002196:Capillaries / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion; D002465:Cell Movement; D002478:Cells, Cultured; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000098:blood supply; D003094:Collagen; D004338:Drug Combinations; D042783:Endothelial Cells / Q000378:metabolism*; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D007797:Laminin; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D018919:Neovascularization, Physiologic; D010766:Phosphorylation; D011509:Proteoglycans; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D051898:Smad1 Protein / Q000378:metabolism; D051902:Smad5 Protein / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D029961:Zebrafish Proteins
chemical_list: C525809:BMP4 protein, human; C476724:BMPER protein, human; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D004338:Drug Combinations; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D007797:Laminin; D011509:Proteoglycans; D034741:RNA, Small Interfering; C497399:SMAD1 protein, human; C497797:SMAD5 protein, human; D051898:Smad1 Protein; D051902:Smad5 Protein; D029961:Zebrafish Proteins; C525813:bmp4 protein, zebrafish; C059485:matrigel; D003094:Collagen; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3