Revealing the role of phospholipase Cβ3 in the regulation of VEGF-induced vascular permeability.
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.
Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Luke H
LH
Hoeppner
Kathryn N
KN
Phoenix
Karl J
KJ
Clark
Resham
R
Bhattacharya
Xun
X
Gong
Tracey E
TE
Sciuto
Pawan
P
Vohra
Sandip
S
Suresh
Santanu
S
Bhattacharya
Ann M
AM
Dvorak
Stephen C
SC
Ekker
Harold F
HF
Dvorak
Kevin P
KP
Claffey
Debabrata
D
Mukhopadhyay
D000818:Animals; D030801:Animals, Genetically Modified; D020013:Calcium Signaling / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects; D002478:Cells, Cultured; D004625:Embryo, Nonmammalian; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D018869:Heat-Shock Response; D057166:High-Throughput Screening Assays; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D060172:Morpholinos / Q000494:pharmacology; D054799:Phospholipase C beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
D018840:HSP70 Heat-Shock Proteins; D060172:Morpholinos; D011994:Recombinant Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D029961:Zebrafish Proteins; D054799:Phospholipase C beta; C518040:Plcb3 protein, mouse