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

• 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

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.

全反式维甲酸（ATRA）是一种天然维甲酸，通过维甲酸受体（RAR）调节多种重要的细胞功能。全反式维甲酸已被用于治疗各种恶性肿瘤，包括急性早幼粒细胞白血病。最近，全反式维甲酸也被认为是有益的动脉粥样硬化血管疾病。然而，其对血管生成的影响仍然存在争议。因此，我们研究了ATRA对体外血管生成的影响，在毛细血管样管的形成方面，使用人脐静脉内皮细胞（HUVEC）/正常人皮肤成纤维细胞（NHDF）共培养。ATRA以及RAR激动剂Am 80显著诱导毛细血管样管形成。与RAR拮抗剂LE 540/LE 135共孵育可抑制ATRA诱导的小管形成。ATRA也诱导HUVEC增殖，但不诱导其迁移。与血管内皮生长因子（VEGF）中和抗体或与VEGF受体（VEGFR）-2（KDR）中和抗体共孵育可完全消除ATRA诱导的管形成，但与VEGFR-1（Flt-1）中和抗体则不能。NHDF中ATRA和Am 80诱导的VEGF基因启动子被ATRA激活，RAR过表达增强。ATRA还诱导HUVEC表达VDGFR-2/KDR mRNA。此外，ATRA诱导分泌肝细胞生长因子（HGF）以及血管生成素-2（Ang-2）的共培养。总之，ATRA可能通过RAR诱导血管生成，主要是通过刺激HUVEC增殖和增强内源性VEGF信号传导，部分是通过诱导HGF和Ang-2产生。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药物。

项目成果

Peroxisome proliferator-activated receptor γ(PPARγ) in human breast carcinoma a modulator of estrogenic actions.

人乳腺癌中的过氧化物酶体增殖物激活受体 γ (PPARγ) 是雌激素作用的调节剂。

• 发表时间: 2006
• 期刊: Endocr Relat Cancer (In press)
• 作者: Suzuki T;Hayashi S;Miki Y;et al.
• 通讯作者: et al.

Peroxisome proliferator-activated receptor γ (PPAR γ) in human breast carcinoma: a possible modulator of estrogenic actions.

人乳腺癌中的过氧化物酶体增殖物激活受体 γ (PPAR γ)：雌激素作用的可能调节剂。

• 发表时间: 2006
• 期刊: Endocr Relat Cancer 13
• 作者: Suzuki T;Hayashi S;Miki Y;Ono K;Nakamura Y;Moriya T;Sugawara A;Ishida T;Ohuchi N;Sasano H
• 通讯作者: Sasano H

糖尿病を有しない低機能性副腎皮質腺腫患者におけるインスリン分泌能・抵抗性の動態。

非糖尿病低功能肾上腺皮质腺瘤患者胰岛素分泌能力和抵抗力的动态变化。

• 发表时间: 2006
• 期刊: ACTH related peptides 17
• 作者: 菅原 明;伊藤貞嘉
• 通讯作者: 伊藤貞嘉

Effects of ATRA and synthetic retinoid Am80 on endothelial gene expression-DNA microarray analyses

ATRA 和合成类视黄醇 Am80 对内皮基因表达的影响 - DNA 微阵列分析

• 发表时间: 2006
• 期刊: Ketsuatsu 13
• 作者: Sugawara A;Saito A;Uruno A;Imaizumi M;Kudo M;Kagechika H;Hongo M;Ito S.
• 通讯作者: Ito S.

3rd report of patients with Cushing''s syndrome who Admitted Tohoku Univ. Hosp.

东北大学就读的库欣综合征患者的第3次报告

• 发表时间: 2008
• 作者: Sugawara A;Ito S
• 通讯作者: Ito S