Abstract
VEGF induces vascular permeability (VP) in ischemic diseases and cancer, leading to many pathophysiological consequences. The molecular mechanisms by which VEGF acts to induce hyperpermeability are poorly understood and in vivo models that easily facilitate real-time, genetic studies of VP do not exist. In the present study, we report a heat-inducible VEGF transgenic zebrafish (Danio rerio) model through which VP can be monitored in real time. Using this approach with morpholino-mediated gene knock-down and knockout mice, we describe a novel role of phospholipase Cβ3 as a negative regulator of VEGF-mediated VP by regulating intracellular Ca2+ release. Our results suggest an important effect of PLCβ3 on VP and provide a new model with which to identify genetic regulators of VP crucial to several disease processes.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Animals, Genetically Modified
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Calcium Signaling / drug effects
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Capillary Permeability* / drug effects
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Cells, Cultured
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Embryo, Nonmammalian
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Endothelium, Vascular / cytology
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Endothelium, Vascular / drug effects
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Endothelium, Vascular / metabolism*
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HSP70 Heat-Shock Proteins / genetics
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HSP70 Heat-Shock Proteins / metabolism
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Heat-Shock Response
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High-Throughput Screening Assays
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Human Umbilical Vein Endothelial Cells / cytology
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Human Umbilical Vein Endothelial Cells / drug effects
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Human Umbilical Vein Endothelial Cells / metabolism
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Humans
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Mice
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Mice, Knockout
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Morpholinos / pharmacology
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Phospholipase C beta / antagonists & inhibitors
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Phospholipase C beta / genetics
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Phospholipase C beta / metabolism*
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Promoter Regions, Genetic / drug effects
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Recombinant Proteins / antagonists & inhibitors
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Recombinant Proteins / metabolism
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Up-Regulation / drug effects
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Vascular Endothelial Growth Factor A / antagonists & inhibitors
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Vascular Endothelial Growth Factor A / genetics
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Vascular Endothelial Growth Factor A / metabolism*
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Zebrafish
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Zebrafish Proteins / genetics
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Zebrafish Proteins / metabolism
Substances
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HSP70 Heat-Shock Proteins
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Morpholinos
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Recombinant Proteins
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VEGFA protein, human
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Vascular Endothelial Growth Factor A
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Zebrafish Proteins
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Phospholipase C beta
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Plcb3 protein, mouse