Histone deacetylases inhibitors as anti-angiogenic agents altering vascular endothelial growth factor signaling.
Angiogenesis is a complex biological process involving the coordinated modulation of many genes. Histone deacetylases (HDAC) are a growing family of enzymes that mediate the availability of chromatin to the transcriptional machinery. Trichostatin-A (TSA) and suberoylanilide hydroxamic acid (SAHA), two HDAC inhibitors known to relieve gene silencing, were evaluated as potential antiangiogenic agents. TSA and SAHA were shown to prevent vascular endothelial growth factor (VEGF)-stimulated human umbilical cord endothelial cells (HUVEC) from invading a type I collagen gel and forming capillary-like structures. SAHA and TSA inhibited the VEGF-induced formation of a CD31-positive capillary-like network in embryoid bodies and inhibited the VEGF-induced angiogenesis in the CAM assay. TSA also prevented, in a dose-response relationship, the sprouting of capillaries from rat aortic rings. TSA inhibited in a dose-dependent and reversible fashion the VEGF-induced expression of VEGF receptors, VEGFR1, VEGFR2, and neuropilin-1. TSA and SAHA upregulated the expression by HUVEC of semaphorin III, a recently described VEGF competitor, at both mRNA and protein levels. This effect was specific to endothelial cells and was not observed in human fibroblasts neither in vascular smooth muscle cells. These observations provide a conspicuous demonstration that HDAC inhibitors are potent anti-angiogenic factors altering VEGF signaling.
Deroanne
Christophe F
CF
Research Center in Experimental Cancerology, University of Liège, Sart-Tilman, B-4000 Liège, Belgium. LCTB@ulg.ac.be
Bonjean
Karine
K
Servotte
Sandrine
S
Devy
Laetitia
L
Colige
Alain
A
Clausse
Nathalie
N
Blacher
Sylvia
S
Verdin
Eric
E
Foidart
Jean-Michel
JM
Nusgens
Betty V
BV
Castronovo
Vincent
V
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics; D002478:Cells, Cultured; D002642:Chick Embryo; D002823:Chorion / Q000098:blood supply / Q000187:drug effects; D016228:Endothelial Growth Factors / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008222:Lymphokines / Q000494:pharmacology*; D008856:Microscopy, Fluorescence; D008858:Microscopy, Phase-Contrast; D009419:Nerve Tissue Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012339:RNA, Ribosomal, 28S / Q000235:genetics; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D040121:Semaphorin-3A; D015398:Signal Transduction / Q000187:drug effects*; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000077337:Vorinostat
D020533:Angiogenesis Inhibitors; D002352:Carrier Proteins; D016228:Endothelial Growth Factors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D008222:Lymphokines; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D012339:RNA, Ribosomal, 28S; C108639:SEMA3A protein, human; C488218:Sema3a protein, rat; D040121:Semaphorin-3A; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C012589:trichostatin A; D000077337:Vorinostat; D006655:Histone Deacetylases