The Retinoid Agonist Tazarotene Promotes Angiogenesis and Wound Healing

• Published in: Molecular therapy 2016-10, Vol.24 (10), p.1745-1759
• Main Authors: Al Haj Zen, Ayman, Nawrot, Dorota A, Howarth, Alison, Caporali, Andrea, Ebner, Daniel, Vernet, Aude, Schneider, Jurgen E, Bhattacharya, Shoumo
• Format: Article
• Language: English
• Subjects: Acids; Acne; Alzheimer's disease; Angiogenesis; Angiogenesis Inducing Agents - administration & dosage; Angiogenesis Inducing Agents - pharmacology; Animals; Blood vessels; Cell Proliferation - drug effects; Cells, Cultured; Disease; Disease Models, Animal; FDA approval; Fibroblasts - cytology; Fibroblasts - drug effects; Fibroblasts - metabolism; Genotype & phenotype; Human Umbilical Vein Endothelial Cells; Humans; Kinases; Medicine; Mice; Morphogenesis; Nicotinic Acids - administration & dosage; Nicotinic Acids - pharmacology; Original; Receptors, Retinoic Acid - metabolism; Signal Transduction; Vascular endothelial growth factor; Wound healing; Wound Healing - drug effects
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1038/mt.2016.153

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.