Histone deacetylases inhibitors as anti-angiogenic agents altering vascular endothelial growth factor signaling
Histone deacetylases inhibitors as anti-angiogenic agents altering vascular endothelial growth factor signaling
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DOI：
10.1038/sj.onc.1205108
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发表时间：
2002-01-17
期刊：
影响因子：
8
通讯作者：
Castronovo, V
中科院分区：
文献类型：
--
作者：
Deroanne, CF;Bonjean, K;Castronovo, V
血管生成是一个复杂的生物学过程，涉及许多基因的协调调节。组蛋白去乙酰化酶（HDAC）是一个不断增长的酶家族，它介导染色质对转录机制的可用性。曲古抑菌素-A（TSA）和辛二酰苯胺异羟肟酸（SAHA），两种HDAC抑制剂，已知缓解基因沉默，被评估为潜在的抗血管生成剂。TSA和SAHA被证明可以防止血管内皮生长因子（VEGF）刺激的人脐带内皮细胞（HUVEC）侵入I型胶原凝胶并形成毛细血管样结构。SAHA和TSA抑制VEGF诱导的CD 31阳性毛细血管样网络在胚状体的形成，并抑制VEGF诱导的血管生成在CAM测定。TSA还以剂量-反应关系阻止大鼠主动脉环毛细血管的发芽。TSA以剂量依赖性和可逆的方式抑制VEGF诱导的VEGF受体、VEGFR 1、VEGFR 2和神经纤毛蛋白-1的表达。TSA和SAHA在mRNA和蛋白质水平上上调HUVEC的semaphorin 111（一种最近描述的VEGF竞争剂）的表达。这种效应对内皮细胞是特异性的，在人成纤维细胞和血管平滑肌细胞中均未观察到。这些观察结果提供了一个显着的证明，HDAC抑制剂是有效的抗血管生成因子：改变VEGF信号。
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.