Differential angiogenic properties of lithium chloride in vitro and in vivo

TY - JOUR

T1 - Differential angiogenic properties of lithium chloride in vitro and in vivo

AU - Zeilbeck, Ludwig F

AU - Müller, Birgit

AU - Knobloch, Verena

AU - Tamm, Ernst R

AU - Ohlmann, Andreas

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

KW - Animals

KW - Cell Movement/drug effects

KW - Cell Proliferation/drug effects

KW - Cell Survival/drug effects

KW - Dermis/blood supply

KW - Endothelial Cells/cytology

KW - Eye Proteins/metabolism

KW - Humans

KW - Indoles/pharmacology

KW - Injections, Intraperitoneal

KW - Lithium Chloride/administration & dosage

KW - Maleimides/pharmacology

KW - Mice

KW - Microvessels/cytology

KW - Neovascularization, Physiologic/drug effects

KW - Nerve Tissue Proteins/metabolism

KW - Oxygen

KW - Retina/drug effects

KW - Vascular Endothelial Growth Factor A/metabolism

KW - Wnt Signaling Pathway/drug effects

U2 - 10.1371/journal.pone.0095546

DO - 10.1371/journal.pone.0095546

M3 - SCORING: Journal article

C2 - 24751879

VL - 9

SP - e95546

JO - PLOS ONE

JF - PLOS ONE

SN - 1932-6203

IS - 4

ER -