Retinoic acid selectively inhibits the vascular permeabilizing effect of VPF/VEGF, an early step in the angiogenic cascade
Retinoic acid selectively inhibits the vascular permeabilizing effect of VPF/VEGF, an early step in the angiogenic cascade
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DOI：
10.1006/mvre.2000.2246
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发表时间：
2000-09-01
影响因子：
3.1
通讯作者：
Mukhopadhyay, D
中科院分区：
文献类型：
--
作者：
Pal, S;Iruela-Arispe, ML;Mukhopadhyay, D
全反式维甲酸（RA）和其他类维甲酸调节细胞生长和分化，一般有利于终末细胞分化和抑制癌变。据报道，类维生素a还能抑制血管生成和内皮细胞迁移，这些作用也具有抗癌作用。血管通透性因子/血管内皮生长因子（VPF/VEGF）是多种肿瘤分泌的多功能细胞因子。它使微血管对血浆具有高渗透性，并刺激内皮细胞迁移和分裂。为了进一步研究RA抑制血管生成的机制，我们评估了RA对VPF/ vegf诱导的血管生成和微血管通透性的影响。在CAM实验中，RA选择性地抑制VPF/VEGF诱导的血管生成反应，但不抑制成纤维细胞生长因子-2 （FGF-2）诱导的血管生成反应。RA及其两种异构体对VPF/VEGF的血管通透作用也有抑制作用，但对组胺诱导的血管通透作用无抑制作用。由VPF/VEGF诱导并被RA阻断的血管通透性在1-15分钟内发生，这一时间太短，RA无法通过经典类视黄醛受体调节转录。RA也抑制VPF/VEGF诱导的plc - γ磷酸化和cGMP合成，但实际上增加了VPF/VEGF与培养内皮细胞的结合。综上所述，这些发现表明RA选择性地阻断VPF/VEGF诱导的微血管通透性和血管生成，并确定VPF/VEGF是RA作用的主要靶点。RA作用的选择性表明，在FGF-2诱导的血管生成和组胺的血管渗透作用中，必须存在其他不依赖RA的途径。(C) 2000年学术出版社。
All-trans-retinoic acid (RA) and other retinoids modulate cell growth and differentiation, generally favoring terminal cell differentiation and inhibiting carcinogenesis. Retinoids are also reported to inhibit angiogenesis and endothelial cell migration, actions that are also anti-carcinogenic. vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) is a multifunctional cytokine secreted by many tumors. It renders microvessels hyperpermeable to plasma and stimulates endothelial cell migration and division. To investigate further the mechanisms by which RA inhibits angiogenesis, we evaluated the effects of RA on VPF/VEGF-induced angiogenesis and-microvascular permeability. RA selectively inhibited the angiogenic response induced by VPF/VEGF, but not that induced by fibroblast growth factor-2 (FGF-2), in the CAM assay. RA and two of its isomers also inhibited the vascular permeabilizing effect of VPF/VEGF but not that induced by histamine. The vascular permeabilization induced by VPF/VEGF and blocked by RA takes place within 1-15 min, too short a time frame for RA to act by modulating transcription through classic retinoid receptors. RA also inhibited VPF/VEGF-induced phosphorylation of PLC-gamma and synthesis of cGMP but actually increased VPF/VEGF binding to cultured endothelial cells. Taken together, these findings indicate that RA selectively blocks VPF/VEGF-induced microvascular permeability and angiogenesis and also identify VPF/VEGF as a major target of RA action. The selectivity of RA's action suggests that other, RA-independent pathways must exist for the angiogenesis induced by FGF-2 and the vascular permeabilizing effect of histamine. (C) 2000 Academic Press.