HDAC5 is a repressor of angiogenesis and determines the angiogenic gene expression pattern of endothelial cells.
Class IIa histone deacetylases (HDACs) are signal-responsive regulators of gene expression involved in vascular homeostasis. To investigate the differential role of class IIa HDACs for the regulation of angiogenesis, we used siRNA to specifically suppress the individual HDAC isoenzymes. Silencing of HDAC5 exhibited a unique pro-angiogenic effect evidenced by increased endothelial cell migration, sprouting, and tube formation. Consistently, overexpression of HDAC5 decreased sprout formation, indicating that HDAC5 is a negative regulator of angiogenesis. The antiangiogenic activity of HDAC5 was independent of myocyte enhancer factor-2 binding and its deacetylase activity but required a nuclear localization indicating that HDAC5 might affect the transcriptional regulation of gene expression. To identify putative HDAC5 targets, we performed microarray expression analysis. Silencing of HDAC5 increased the expression of fibroblast growth factor 2 (FGF2) and angiogenic guidance factors, including Slit2. Antagonization of FGF2 or Slit2 reduced sprout induction in response to HDAC5 siRNA. Chromatin immunoprecipitation assays demonstrate that HDAC5 binds to the promoter of FGF2 and Slit2. In summary, HDAC5 represses angiogenic genes, such as FGF2 and Slit2, which causally contribute to capillary-like sprouting of endothelial cells. The derepression of angiogenic genes by HDAC5 inactivation may provide a useful therapeutic target for induction of angiogenesis.
Molecular Cardiology, Department of Medicine III, University of Frankfurt, Frankfurt, Germany.
Carmen
C
Urbich
Lothar
L
Rössig
David
D
Kaluza
Michael
M
Potente
Jes-Niels
JN
Boeckel
Andrea
A
Knau
Florian
F
Diehl
Jian-Guo
JG
Geng
Wolf-Karsten
WK
Hofmann
Andreas M
AM
Zeiher
Stefanie
S
Dimmeler
D020533:Angiogenesis Inhibitors / Q000037:antagonists & inhibitors / Q000502:physiology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000502:physiology; D008954:Models, Biological; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D034741:RNA, Small Interfering / Q000494:pharmacology; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D000098552:Slit Homolog 2 Protein
D020533:Angiogenesis Inhibitors; D056572:Histone Deacetylase Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; D007527:Isoenzymes; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D016222:Fibroblast Growth Factor 2; C404500:HDAC5 protein, human; D006655:Histone Deacetylases; D000098552:Slit Homolog 2 Protein