This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 103/8/804    most recent CIRCRESAHA.108.178434v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Heinke, J. Articles by Moser, M. Search for Related Content PubMed PubMed Citation Articles by Heinke, J. Articles by Moser, M. Pubmed/NCBI databases Gene GEO Profiles HomoloGene OMIM Protein UniGene Substance via MeSH Related Collections Angiogenesis Endothelium/vascular type/nitric oxide Mechanism of atherosclerosis/growth factors

(Circulation Research. 2008;103:804.)
© 2008 American Heart Association, Inc.

Molecular Medicine

BMPER Is an Endothelial Cell Regulator and Controls Bone Morphogenetic Protein-4–Dependent Angiogenesis

Jennifer Heinke, Leonie Wehofsits, Qian Zhou, Christoph Zoeller, Kim-Miriam Baar, Thomas Helbing, Anna Laib, Hellmut Augustin, Christoph Bode, Cam Patterson, Martin Moser

From the Departments of Cardiology (J.H., L.W., Q.Z., C.Z., K.-M.B., T.H., C.B., M.M.) and Biology (J.H., K.-M.B.), University of Freiburg, Germany; German Center for Cancer Research (A.L., H.A.), Heidelberg, Germany; and Carolina Cardiovascular Biology Center (C.P.), University of North Carolina, Chapel Hill.

Correspondence to Martin Moser, University of Freiburg, Department of Cardiology, Hugstetter Strasse 55, 79106 Freiburg, Germany. E-mail Martin.Moser{at}uniklinik-freiburg.de

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.

Key Words: BMPER • bone morphogenetic proteins • vascular biology • endothelial cell function • signaling

This article has been cited by other articles:

				D. Umulis, M. B. O'Connor, and S. S. Blair The extracellular regulation of bone morphogenetic protein signaling Development, November 15, 2009; 136(22): 3715 - 3728. [Abstract] [Full Text] [PDF]

				T. Helbing, F. Volkmar, U. Goebel, J. Heinke, P. Diehl, H. L. Pahl, C. Bode, C. Patterson, and M. Moser Kruppel-like factor 15 regulates BMPER in endothelial cells Cardiovasc Res, October 18, 2009; (2009) cvp314v2. [Abstract] [Full Text] [PDF]

				Y. Yao, A. D. Watson, S. Ji, and K. I. Bostrom Heat Shock Protein 70 Enhances Vascular Bone Morphogenetic Protein-4 Signaling by Binding Matrix Gla Protein Circ. Res., September 11, 2009; 105(6): 575 - 584. [Abstract] [Full Text] [PDF]

				E. S. Shao, L. Lin, Y. Yao, and K. I. Bostrom Expression of vascular endothelial growth factor is coordinately regulated by the activin-like kinase receptors 1 and 5 in endothelial cells Blood, September 3, 2009; 114(10): 2197 - 2206. [Abstract] [Full Text] [PDF]

				X. Sui, D. Li, H. Qiu, V. Gaussin, and C. Depre Activation of the Bone Morphogenetic Protein Receptor by H11Kinase/Hsp22 Promotes Cardiac Cell Growth and Survival Circ. Res., April 10, 2009; 104(7): 887 - 895. [Abstract] [Full Text] [PDF]