Histone deacetylase activity is essential for the expression of HoxA9 and for endothelial commitment of progenitor cells.
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-R2, 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.
Rössig
Lothar
L
Molecular Cardiology, Department of Internal Medicine III, University of Frankfurt, 60590 Frankfurt am Main, Germany.
Urbich
Carmen
C
Brühl
Thomas
T
Dernbach
Elisabeth
E
Heeschen
Christopher
C
Chavakis
Emmanouil
E
Sasaki
Ken-ichiro
K
Aicher
Diana
D
Diehl
Florian
F
Seeger
Florian
F
Potente
Michael
M
Aicher
Alexandra
A
Zanetta
Lucia
L
Dejana
Elisabetta
E
Zeiher
Andreas M
AM
Dimmeler
Stefanie
S
D000818:Animals; D015703:Antigens, CD; D015820:Cadherins / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology*; D005312:Fetal Blood / Q000166:cytology / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology*; D006655:Histone Deacetylases / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D007511:Ischemia / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000235:genetics / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D013314:Stress, Mechanical; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D000099152:Cadherin 5
D015703:Antigens, CD; D015820:Cadherins; D006655:Histone Deacetylases; D018398:Homeodomain Proteins; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D040301:Vascular Endothelial Growth Factor Receptor-2; D000099152:Cadherin 5; C097899:homeobox protein HOXA9; C496314:NOS3 protein, human; C496315:Nos3 protein, mouse