Differential angiogenic properties of lithium chloride in vitro and in vivo

• Published in: PloS one 2014-04, Vol.9 (4), p.e95546-e95546
• Main Authors: Zeilbeck, Ludwig F, Müller, Birgit, Knobloch, Verena, Tamm, Ernst R, Ohlmann, Andreas
• Format: Article
• Language: English
• Subjects: Analysis; Angiogenesis; Animals; Biology and Life Sciences; Catenanes; Cell Movement - drug effects; Cell Proliferation - drug effects; Cell Survival - drug effects; Chlorides; Dermis - blood supply; Diabetes; Diabetic retinopathy; Dichloropropane; Embryology; Endothelial cells; Endothelial Cells - cytology; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Eye Proteins - metabolism; Frizzled protein; Humans; Indoles - pharmacology; Injections, Intraperitoneal; Ischemia; Kinases; Lithium; Lithium chloride; Lithium Chloride - administration & dosage; Lithium Chloride - pharmacology; Lithium compounds; Maleimides - pharmacology; Medicine and Health Sciences; Mice; Microvasculature; Microvessels - cytology; Neovascularization, Physiologic - drug effects; Nerve Tissue Proteins - metabolism; Nuclear transport; Oxygen; Properties; Proteins; Quercetin; Repair; Research and Analysis Methods; Retina; Retina - drug effects; Retina - metabolism; Retina - pathology; Retinopathy; Rodents; Signal transduction; Signaling; Stroke; Translocation; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - metabolism; Wnt protein; Wnt Signaling Pathway - drug effects; β-Catenin
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0095546

Wnt/β-catenin signaling induced by the Norrin/Frizzled-4 pathway has been shown to improve capillary repair following oxygen induced retinopathy (OIR) in the mouse, a model for retinopathy of prematurity. Here we investigated if treatment with the monovalent cation lithium that has been shown to augment Wnt/β-catenin signaling in vitro and in vivo has similar effects. In cultured human microvascular endothelial cells, LiCl as well as SB 216763, another small molecule that activates Wnt/β-catenin signaling, induced proliferation, survival and migration, which are all common parameters for angiogenic properties in vitro. Moreover, treatment with both agents caused an increase in the levels of β-catenin and their translocation to nuclei while quercetin, an inhibitor of Wnt/β-catenin signaling, completely blocked the effects of LiCl on proliferation. In mice with OIR, intraperitonal or intravitreal treatment with LiCl markedly increased the retinal levels of β-catenin, but did not improve capillary repair. In contrast, repair was significantly improved following intravitreal treatment with Norrin. The effects of LiCl on HDMEC in vitro have minor relevance for OIR in vivo, and the influence of the Norrin/Frizzled-4 pathway on capillary repair in OIR is not reproducible upon enhancing Wnt/β-catenin signaling by LiCl treatment strongly indicating the presence of additional and essential mechanisms.