All-trans retinoic acid induces in vitro angiogenesis via retinoic acid receptor:: Possible involvement of paracrine effects of endogenous vascular endothelial growth factor signaling
All-trans retinoic acid induces in vitro angiogenesis via retinoic acid receptor:: Possible involvement of paracrine effects of endogenous vascular endothelial growth factor signaling
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DOI：
10.1210/en.2006-0900
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发表时间：
2007-03-01
期刊：
影响因子：
4.8
通讯作者：
Ito, Sadayoshi
中科院分区：
文献类型：
--
作者：
Saito, Akiko;Sugawara, Akira;Ito, Sadayoshi
天然全反式维甲酸(ATRA)通过维甲酸受体(RAR)调节多种重要的细胞功能。全反式维甲酸已用于治疗包括急性早幼粒细胞白血病在内的多种恶性肿瘤。最近，全反式维甲酸也被认为对动脉粥样硬化性血管疾病有好处。然而，它对血管生成的影响仍然存在争议。因此，我们使用人脐静脉内皮细胞(HUVECs)和正常人真皮成纤维细胞(NHDF)共培养，通过毛细血管样管的形成来检测ATRA对体外血管生成的影响。ATRA和RAR激动剂AM80均能显著诱导毛细血管样管形成。与RAR拮抗剂LE540/LE135共同孵育可抑制ATRA诱导的小管形成。ATRA也能诱导HUVEC增殖，但不能诱导其迁移。与血管内皮生长因子(VEGFR)-2(KDR)中和抗体或VEGFR-1(Flt-1)中和抗体共同孵育后，ATRA诱导的小管形成完全消失。ATRA和Am80可诱导NHDF分泌血管内皮生长因子和表达血管内皮生长因子。全反式维甲酸可刺激人血管内皮生长因子基因启动子在NHDF中的转录活性，RAR过表达可增强其转录活性。ATRA还可诱导人脐静脉内皮细胞VDGFR-2/KDR基因表达。此外，ATRA还可诱导共培养细胞分泌肝细胞生长因子和血管生成素-2。综上所述，ATRA可能主要通过刺激HUVEC增殖和增强内源性血管内皮生长因子信号转导途径，部分通过诱导肝细胞生长因子和血管生成素-2的产生，通过RAR诱导血管生成。因此，维甲酸可能是治疗缺血性血管疾病血管生成的潜在候选者。
A natural retinoid all-trans retinoic acid ( ATRA) regulates a variety of important cellular functions via retinoic acid receptor ( RAR). ATRA has therapeutically been used against various malignancies including acute promyelocytic leukemia. Recently ATRA has also been recognized to be beneficial against atherosclerotic vascular disorders. However, its effects on angiogenesis remain controversial. We therefore examined ATRA effects on in vitro angiogenesis in terms of capillary-like tube formation using human umbilical vein endothelial cells ( HUVECs)/ normal human dermal fibroblast ( NHDF) coculture. ATRA as well as RAR agonist Am80 significantly induced capillary-like tube formation. The ATRA- induced tube formation was inhibited by coincubation with RAR antagonist LE540/ LE135. HUVEC proliferation, but not its migration, was also induced by ATRA. The ATRA- induced tube formation was completely abolished by coincubation with vascular endothelial growth factor ( VEGF) neutralizing antibody or with VEGF receptor ( VEGFR)- 2 ( KDR) neutralizing antibody, but not VEGFR-1 ( Flt-1) neutralizing antibody. ATRA and Am80 induced VEGF secretion in the coculture as well as VEGF secretion/ mRNA expression in NHDFs. Transcription activity of human VEGF gene promoter in NHDFs was stimulated by ATRA, which was augmented by RAR overexpression. ATRA also induced VDGFR-2/ KDR mRNA expression in HUVECs. Moreover, ATRA- induced secretion of hepatocyte growth factor as well as angiopoietin-2 in the coculture. Taken together, ATRA may have induced angiogenesis via RAR mainly by stimulation of HUVEC proliferation and enhancement of endogenous VEGF signaling and in part by induction of hepatocyte growth factor and angiopoietin-2 production. Retinoids may therefore be potential candidates for therapeutic angiogenesis against ischemic vascular disorders.