Histone deacetylases inhibitors as anti-angiogenic agents altering vascular endothelial growth factor signaling

被引:344
作者
Deroanne, CF
Bonjean, K
Servotte, S
Devy, L
Colige, A
Clausse, N
Blacher, S
Verdin, E
Foidart, JM
Nusgens, BV
Castronovo, V
机构
[1] Univ Liege, Lab Connect Tissues Biol, B-4000 Liege, Sart Tilman, Belgium
[2] Univ Liege, Res Ctr Expt Cancerol, B-4000 Liege, Belgium
[3] Univ Liege, Lab Metastasis Res, B-4000 Liege, Belgium
[4] Univ Liege, Lab Tumor & Dev Biol, B-4000 Liege, Belgium
[5] Univ Calif San Francisco, San Francisco, CA 94143 USA
[6] Gladstone Inst Virol & Immunol, San Francisco, CA USA
关键词
angiogenesis; trichostatin A; suberoylanilide hydroxamic acid; VEGF; neuropilin-1; semaphorin III;
D O I
10.1038/sj.onc.1205108
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 111, 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.
引用
收藏
页码:427 / 436
页数:10
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