9-cis retinoic acid promotes lymphangiogenesis and enhances lymphatic vessel regeneration: therapeutic implications of 9-cis retinoic acid for secondary lymphedema.
9-cis retinoic acid promotes lymphangiogenesis and enhances lymphatic vessel regeneration: therapeutic implications of 9-cis retinoic acid for secondary lymphedema.
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DOI：
10.1161/circulationaha.111.030296
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发表时间：
2012-02-21
期刊：
影响因子：
37.8
通讯作者：
Hong YK
中科院分区：
文献类型：
--
作者：
Choi I;Lee S;Kyoung Chung H;Suk Lee Y;Eui Kim K;Choi D;Park EK;Yang D;Ecoiffier T;Monahan J;Chen W;Aguilar B;Lee HN;Yoo J;Koh CJ;Chen L;Wong AK;Hong YK
淋巴系统在组织液稳态中起着关键作用，由于遗传缺陷或淋巴管阻塞而导致的淋巴功能障碍可导致淋巴水肿、组织肿胀，通常与纤维化和反复感染有关，迄今尚无有效的治疗方法。在这项研究中，维甲酸(RAS)被确定为一种立即适用于减少继发性淋巴水肿的有效治疗剂。我们报道RAS通过激活成纤维细胞生长因子受体信号促进淋巴管内皮细胞的增殖、迁移和管状形成。此外，RAS通过Akt介导的非基因组作用和由淋巴管发育的主要调节因子Prox1介导的转录依赖的基因组作用，控制细胞周期检查点调节因子p27Kip1、p57Kip2和极光蛋白的表达。此外，基于小鼠气管、Matrigel Plug和角膜口袋试验，9-Cisra被发现在动物体内激活淋巴管生成。最后，我们证明了9-Cisra可以通过促进淋巴管再生来改善实验性小鼠尾部淋巴水肿。这些体外和动物研究表明，9-Cisra在实验性淋巴水肿模型中有效地激活淋巴管生成并促进淋巴再生，为治疗人类淋巴水肿患者提供了一种有前途的新型治疗剂。
The lymphatic system plays a key role in tissue fluid homeostasis and lymphatic dysfunction due to genetic defects or lymphatic vessel obstruction can cause lymphedema, disfiguring tissue swellings often associated with fibrosis and recurrent infections without available cures to date. In this study, retinoic acids (RAs) were determined to be a potent therapeutic agent that is immediately applicable to reduce secondary lymphedema. We report that RAs promote proliferation, migration and tube formation of cultured lymphatic endothelial cells (LECs) by activating FGF-receptor signaling. Moreover, RAs control the expression of cell-cycle checkpoint regulators such as p27Kip1, p57Kip2 and the aurora kinases through both an Akt-mediated non-genomic action and a transcription-dependent genomic action that is mediated by Prox1, a master regulator of lymphatic development. Moreover, 9-cisRA was found to activate in vivo lymphangiogenesis in animals based on mouse trachea, matrigel plug and cornea pocket assays. Finally, we demonstrate that 9-cisRA can provide a strong therapeutic efficacy in ameliorating the experimental mouse tail lymphedema by enhancing lymphatic vessel regeneration. These in vitro and animal studies demonstrate that 9-cisRA potently activates lymphangiogenesis and promotes lymphatic regeneration in an experimental lymphedema model, presenting it as a promising novel therapeutic agent to treat human lymphedema patients.