The Retinoid Agonist Tazarotene Promotes Angiogenesis and Wound Healing

Abstract

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.

Multi-Parametric Profiling of Endothelial Cell Networks Reveals Functional Role of Glutamate Receptors in Angiogenesis

“…1D). Moreover, 95% of the drugs that were identified as inhibitors in the previous study (Al Haj Zen et al, 2016) are in this cluster (75/79 Fisher exact test;.…”

“…To comprehensively profile endothelial network patterns upon drug treatments, we used a dataset from a previous high content screen of LOPAC1280 small molecule library (Al Haj Zen et al, 2016). In the previous study, we identified 15 enhancers and 79 inhibitors of tube formation where the analysis have been limited to one feature of the network (total tube length).…”

“…The dataset used in this study was generated by an image-based screen of 1280 compounds based on LOPAC library as described previously (Al Haj Zen et al, 2016). Briefly, HUVEC endothelial cells were cultured on top of Matrigel after adding compounds and incubated at 37°C, 5% CO2 for 8 hours.…”

“…The screening of more complex cell culture models that mimic in vivo biology is starting to emerge as it is expected to select drugs that are more likely to mature in the clinic (Mills et al, 2019;Tung et al, 2011). Although vascular morphogenesis assays have been established (Al Haj Zen et al, 2016;Isherwood et al, 2013), a comprehensive analysis of these complex culture models are still lacking. Moreover, the extent that higher level tissue properties reflect those at the molecular level is yet to be established.…”

Retinoic acid signaling in vascular development

“…Several studies report RA exposure inhibits tumor angiogenesis in a variety of cancers (Gee et al, 2005;Hoffmann et al, 2007;Kini, Peterson, Tallman, & Lingen, 2001;Lingen, Polverini, & Bouck, 1998;Majewski, Szmurlo, Marczak, Jablonska, & Bollag, 1993). That said, pro-angiogenic properties of RA or RAR-agonists have also been documented (Lansink, Koolwijk, van Hinsbergh, & Kooistra, 1998), often via upregulation of VEGFA (Al Haj Zen et al, 2016;Saito et al, 2007;Wang et al, 2014) or FGF ligands (Gaetano et al, 2001). This apparent dual nature of RA with regard to angiogenesis may reflect the cell-type specific nature of RA signaling pathways (e.g.…”