Dataset Information

PP2A regulatory subunit B? controls endothelial contractility and vessel lumen integrity via regulation of HDAC7.

ABSTRACT: 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 B? regulatory subunit of protein phosphatase 2A (PP2A). Deficiency of B? in zebrafish precludes vascular lumen stabilization resulting in perfusion defects. Similarly, inactivation of PP2A-B? 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-B? controls the activity of HDAC7, an essential transcriptional regulator of vascular stability. In the absence of PP2A-B?, 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-B?/HDAC7/ArgBP2 axis maintains vascular lumens by balancing endothelial cytoskeletal dynamics and cell-matrix adhesion.

SUBMITTER: Martin M

PROVIDER: S-EPMC3770954 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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PP2A regulatory subunit Bα controls endothelial contractility and vessel lumen integrity via regulation of HDAC7.

Martin Maud M Geudens Ilse I Bruyr Jonathan J Potente Michael M Bleuart Anouk A Lebrun Marielle M Simonis Nicolas N Deroanne Christophe C Twizere Jean-Claude JC Soubeyran Philippe P Peixoto Paul P Mottet Denis D Janssens Veerle V Hofmann Wolf-Karsten WK Claes Filip F Carmeliet Peter P Kettmann Richard R Gerhardt Holger H Dequiedt Franck F

The EMBO journal 20130816 18

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 Bα regulatory subunit of protein phosphatase 2A (PP2A). Deficiency of Bα in zebrafish precludes vascular lumen stabilization resulting in perfusion defects. Similarly, inactivation of PP2A-Bα in cultured ECs induces tubulogenesis failure due to alteration of cytoskeleton dynamics, actomyos ...[more]

PMID: 23955003

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Project description:Rasa3 is a GTPase activating protein of the GAP1 family which targets R-Ras and Rap1. Although catalytic inactivation or deletion of Rasa3 in mice leads to severe hemorrhages and embryonic lethality, the biological function and cellular location of Rasa3 underlying these defects remains unknown. Here, using a combination of loss of function studies in mouse and zebrafish as well as in vitro cell biology approaches, we identify a key role for Rasa3 in endothelial cells and vascular lumen integrity. Specific ablation of Rasa3 in the mouse endothelium, but not in megakaryocytes and platelets, lead to embryonic bleeding and death at mid-gestation, recapitulating the phenotype observed in full Rasa3 knock-out mice. Reduced plexus/sprouts formation and vascular lumenization defects were observed when Rasa3 was specifically inactivated in mouse endothelial cells at the postnatal or adult stages. Similar results were obtained in zebrafish after decreasing Rasa3 expression. In vitro, depletion of Rasa3 in cultured endothelial cells increased ?1 integrin activation and cell adhesion to extracellular matrix components, decreased cell migration and blocked tubulogenesis. During migration, these Rasa3-depleted cells exhibited larger and more mature adhesions resulting from a perturbed dynamics of adhesion assembly and disassembly which significantly increased their life time. These defects were due to a hyperactivation of the Rap1 GTPase and blockade of FAK/Src signaling. Finally, Rasa3-depleted cells showed reduced turnover of VE-cadherin-based adhesions resulting in more stable endothelial cell-cell adhesion and decreased endothelial permeability. Altogether, our results indicate that Rasa3 is a critical regulator of Rap1 in endothelial cells which controls adhesions properties and vascular lumen integrity; its specific endothelial cell inactivation results in occluded blood vessels, hemorrhages and early embryonic death in mouse, mimicking thus the Rasa3-/- mouse phenotype.

Dataset Information

PP2A regulatory subunit B? controls endothelial contractility and vessel lumen integrity via regulation of HDAC7.

Publications

PP2A regulatory subunit Bα controls endothelial contractility and vessel lumen integrity via regulation of HDAC7.

Similar Datasets

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