EFFECTS OF ALL-TRANS RETINOIC ACID AND RETINOIDS ON ANGIOGENESIS

全反式视黄酸和类视黄醇对血管生成的影响

基本信息

批准号：
18591015
负责人：
SUGAWARA Akira
金额：
$ 2.43万
依托单位：
Tohoku University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18591015/
关键词：
all-trans retinoic acid retinoic acid receptor angiogenesis retinoid endothelial cells all-trans retinoic acid retinoic acid receptor angiogenesis retinoid endothelial cells 血管内皮増殖因子動脈硬化受容体

项目摘要

A natural retinoid all-trans retinoic acid (ATRA) regulates a variety of important cellular functions via retinoic acid receptor (RAR). ATRA has therapeutically been utilized 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 (HUVEC)/normal human dermal fibroblasts (NHDF) co-culture. ATRA as well as RAR agonist Am80 significantly induced capillary-like tube formation. The ATRA-induced tube formation was inhibited by co-incubation 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 co-incubation with vascular endothelial growth factor (VEGF) neutralizing antibody or with VEGF receptor (VEGFR)-2 (KDR) neutralizing antibody, but not with VEGFR-1 (Flt-1) neutralizing antibody. ATRA and Am80 induced VEGF gene promoter in NHDF was stimulated by ATRA, which was augmented by RAR overexpression. ATRA also induced VDGFR-2/KDR mRNA expression in HUVEC. Moreover, ATRA induced secretion of hepatocyte growth factor (HGF) as well as angiopoietin-2 (Ang-2) in the co-culture. 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 HGF and Ang-2 production. Retinoids may therefore be potential candiadates for therapeutic angiogenesis against ischemic vascular disorders.

天然类视黄醇全反式视黄酸 (ATRA) 通过视黄酸受体 (RAR) 调节多种重要的细胞功能。 ATRA 已用于治疗多种恶性肿瘤，包括急性早幼粒细胞白血病。最近，ATRA 也被认为有益于对抗动脉粥样硬化性血管疾病。然而，其对血管生成的影响仍存在争议。因此，我们使用人脐静脉内皮细胞 (HUVEC)/正常人真皮成纤维细胞 (NHDF) 共培养，在毛细血管样管形成方面检查了 ATRA 对体外血管生成的影响。 ATRA 和 RAR 激动剂 Am80 显着诱导毛细管样管形成。与 RAR 拮抗剂 LE540/LE135 共孵育可抑制 ATRA 诱导的管形成。 ATRA 也诱导 HUVEC 增殖，但不诱导其迁移。通过与血管内皮生长因子 (VEGF) 中和抗体或 VEGF 受体 (VEGFR)-2 (KDR) 中和抗体共孵育，ATRA 诱导的管形成被完全消除，但与 VEGFR-1 (Flt-1) 中和抗体共孵育则不会。抗体。 ATRA 和 Am80 诱导 NHDF 中的 VEGF 基因启动子受到 ATRA 的刺激，并通过 RAR 的过表达而增强。 ATRA 还诱导 HUVEC 中 VDGFR-2/KDR mRNA 的表达。此外，ATRA 诱导共培养物中肝细胞生长因子 (HGF) 和血管生成素-2 (Ang-2) 的分泌。总而言之，ATRA 可能主要通过刺激 HUVEC 增殖和增强内源 VEGF 信号传导，以及部分通过诱导 HGF 和 Ang-2 产生，通过 RAR 诱导血管生成。因此，类维生素A可能是治疗缺血性血管疾病的血管生成的潜在候选者。