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Histone deacetylase activity is essential for the expression of HoxA9 and for endothelial commitment of progenitor cells

Item Type:Article
Title:Histone deacetylase activity is essential for the expression of HoxA9 and for endothelial commitment of progenitor cells
Creators Name:Rössig, L. and Urbich, C. and Brühl, T. and Dernbach, E. and Heeschen, C. and Chavakis, E. and Sasaki, K.I. and Aicher, D. and Diehl, F. and Seeger, F. and Potente, M. and Aicher, A. and Zanetta, L. and Dejana, E. and Zeiher, A.M. and Dimmeler, S.
Abstract:The regulation of acetylation is central for the epigenetic control of lineage-specific gene expression and determines cell fate decisions. We provide evidence that the inhibition of histone deacetylases (HDACs) blocks the endothelial differentiation of adult progenitor cells. To define the mechanisms by which HDAC inhibition prevents endothelial differentiation, we determined the expression of homeobox transcription factors and demonstrated that HoxA9 expression is down-regulated by HDAC inhibitors. The causal involvement of HoxA9 in the endothelial differentiation of adult progenitor cells is supported by the finding that HoxA9 overexpression partially rescued the endothelial differentiation blockade induced by HDAC inhibitors. Knockdown and overexpression studies revealed that HoxA9 acts as a master switch to regulate the expression of prototypical endothelial-committed genes such as endothelial nitric oxide synthase, VEGF-R(2), and VE-cadherin, and mediates the shear stress-induced maturation of endothelial cells. Consistently, HoxA9-deficient mice exhibited lower numbers of endothelial progenitor cells and showed an impaired postnatal neovascularization capacity after the induction of ischemia. Thus, HoxA9 is regulated by HDACs and is critical for postnatal neovascularization.
Keywords:Cadherins, CD Antigens, Cell Differentiation, Cultured Cells, Endothelial Cells, Fetal Blood, Gene Expression Regulation, Hematopoietic Stem Cell, Histone Deacetylases, Homeodomain Proteins, Ischemia, Knockout Mice, Mechanical Stress, Nitric Oxide Synthase, Physiologic Neovascularization, Vascular Endothelial Growth Factor Receptor-2, Animals, Mice
Source:Journal of Experimental Medicine
Publisher:Rockefeller University Press
Page Range:1825-35
Date:6 June 2005
Official Publication:https://doi.org/10.1084/jem.20042097
External Fulltext:View full text on PubMed Central
PubMed:View item in PubMed

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