Al Haj Zen Ayman, Nawrot Dorota A, Howarth Alison, Caporali Andrea, Ebner Daniel, Vernet Aude, Schneider Jurgen E, Bhattacharya Shoumo
Wellcome Trust Centre For Human Genetics, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
BHF Centre of Research Excellence, University of Oxford, Oxford, UK.
Mol Ther. 2016 Oct;24(10):1745-1759. doi: 10.1038/mt.2016.153. Epub 2016 Aug 2.
Therapeutic angiogenesis is a major goal of regenerative medicine, but no clinically approved small molecule exists that enhances new blood vessel formation. Here we show, using a phenotype-driven high-content imaging screen of an annotated chemical library of 1,280 bioactive small molecules, that the retinoid agonist Tazarotene, enhances in vitro angiogenesis, promoting branching morphogenesis, and tubule remodeling. The proangiogenic phenotype is mediated by retinoic acid receptor but not retinoic X receptor activation, and is characterized by secretion of the proangiogenic factors hepatocyte growth factor, vascular endothelial growth factor, plasminogen activator, urokinase and placental growth factor, and reduced secretion of the antiangiogenic factor pentraxin-3 from adjacent fibroblasts. In vivo, Tazarotene enhanced the growth of mature and functional microvessels in Matrigel implants and wound healing models, and increased blood flow. Notably, in ear punch wound healing model, Tazarotene promoted tissue repair characterized by rapid ear punch closure with normal-appearing skin containing new hair follicles, and maturing collagen fibers. Our study suggests that Tazarotene, an FDA-approved small molecule, could be potentially exploited for therapeutic applications in neovascularization and wound healing.
治疗性血管生成是再生医学的一个主要目标，但目前尚无经临床批准的可增强新血管形成的小分子药物。在此，我们通过对一个包含1280种生物活性小分子的注释化学文库进行表型驱动的高内涵成像筛选，发现维甲酸激动剂他扎罗汀可增强体外血管生成，促进分支形态发生和小管重塑。促血管生成表型是由维甲酸受体而非维甲酸X受体激活介导的，其特征是促血管生成因子肝细胞生长因子、血管内皮生长因子、纤溶酶原激活剂、尿激酶和胎盘生长因子的分泌增加，以及相邻成纤维细胞抗血管生成因子五聚素-3的分泌减少。在体内，他扎罗汀可促进基质胶植入物和伤口愈合模型中成熟且有功能的微血管生长，并增加血流量。值得注意的是，在耳打孔伤口愈合模型中，他扎罗汀可促进组织修复，其特征是耳打孔迅速闭合，愈合后的皮肤外观正常，有新的毛囊，胶原纤维成熟。我们的研究表明，他扎罗汀这种已获美国食品药品监督管理局批准的小分子药物，有望用于血管新生和伤口愈合的治疗应用。
