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          Institute: MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut)     Collection: Yearbook_2014     Display Documents

ID: 682185.0, MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut) / Yearbook_2014
PP2A regulatory subunit Balpha controls endothelial contractility and vessel lumen integrity via regulation of HDAC7
Authors:Martin, M.; Geudens, I.; Bruyr, J.; Potente, M.; Bleuart, A.; Lebrun, M.; Simonis, N.; Deroanne, C.; Twizere, J. C.; Soubeyran, P.; Peixoto, P.; Mottet, D.; Janssens, V.; Hofmann, W. K.; Claes, F.; Carmeliet, P.; Kettmann, R.; Gerhardt, H.; Dequiedt, F.
Date of Publication (YYYY-MM-DD):2013-09-11
Journal Abbrev.:Embo j
Issue / Number:18
Start Page:2491
End Page:2503
Audience:Not Specified
Abstract / Description:To supply tissues with nutrients and oxygen, the cardiovascular system forms a seamless, hierarchically branched, network of lumenized tubes. Here, we show that maintenance of patent vessel lumens requires the Balpha regulatory subunit of protein phosphatase 2A (PP2A). Deficiency of Balpha in zebrafish precludes vascular lumen stabilization resulting in perfusion defects. Similarly, inactivation of PP2A-Balpha in cultured ECs induces tubulogenesis failure due to alteration of cytoskeleton dynamics, actomyosin contractility and maturation of cell-extracellular matrix (ECM) contacts. Mechanistically, we show that PP2A-Balpha controls the activity of HDAC7, an essential transcriptional regulator of vascular stability. In the absence of PP2A-Balpha, transcriptional repression by HDAC7 is abrogated leading to enhanced expression of the cytoskeleton adaptor protein ArgBP2. ArgBP2 hyperactivates RhoA causing inadequate rearrangements of the EC actomyosin cytoskeleton. This study unravels the first specific role for a PP2A holoenzyme in development: the PP2A-Balpha/HDAC7/ArgBP2 axis maintains vascular lumens by balancing endothelial cytoskeletal dynamics and cell-matrix adhesion.
Free Keywords:Animals; Cell Adhesion/physiology; Collagen; Drug Combinations; Endothelium, Vascular/*physiology; Fluorescent Antibody Technique; Gene Expression Regulation/genetics/*physiology; Histone Deacetylases/*metabolism; Homeodomain Proteins/metabolism; Human Umbilical Vein Endothelial Cells; Humans; Image Processing, Computer-Assisted; Laminin; Microscopy, Confocal; Neovascularization, Physiologic/*physiology; Protein Phosphatase 2/*metabolism; Proteoglycans; RNA, Small Interfering/genetics; Vascular Patency/genetics/*physiology; Zebrafish
External Publication Status:published
Document Type:Article
Communicated by:Svea Hümmer
Affiliations:MPI für physiologische und klinische Forschung
External Affiliations:%W NLM %G eng
Identifiers:ISSN:0261-4189 %R 10.1038/emboj.2013.187
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