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The Journal of Neuroscience, April 21, 2004, 24(16):4092-4103; doi:10.1523/JNEUROSCI.4252-03.2004

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Development/Plasticity/Repair
Verge: A Novel Vascular Early Response Gene

Jean B. Regard,¹ Sigrid Scheek,⁵ Talaibek Borbiev,⁴ Anthony A. Lanahan,¹ Armin Schneider,⁵ Anna-Maria Demetriades,³ Holger Hiemisch,⁵ Carol A. Barnes,⁶ Alexander D. Verin,⁴ and Paul F. Worley^1,2

Departments of ¹Neuroscience, ²Neurology, and ³Ophthalmology, ⁴Division of Pulmonary and Critical Care, Johns Hopkins University, Baltimore, Maryland 21205, ⁵Axaron Bioscience, 69120 Heidelberg, Germany, and ⁶Departments of Psychology and Neurology, University of Arizona, Tucson, Arizona 85724

Vascular endothelium forms a continuous, semipermeable barrier that regulates the transvascular movement of hormones, macromolecules, and other solutes. Here, we describe a novel immediate early gene that is expressed selectively in vascular endothelial cells, verge (vascular early response gene). Verge protein includes an N-terminal region of 70 amino acids with modest homology (30% identity) to Apolipoprotein L but is otherwise unique. Verge mRNA and protein are induced selectively in the endothelium of adult vasculature by electrical or chemical seizures. Verge expression appears to be responsive to local tissue conditions, because it is induced in the hemisphere ipsilateral to transient focal cerebral ischemia. In contrast to the transient expression in adult, Verge mRNA and protein are constitutively expressed at high levels in the endothelium of developing tissues (particularly heart) in association with angiogenesis. Verge mRNA is induced in cultured endothelial cells by defined growth factors and hypoxia. Verge protein is dramatically increased by cysteine proteinase inhibitors, suggesting rapid turnover, and is localized to focal regions near the periphery of the cells. Endothelial cell lines that stably express Verge form monolayers that show enhanced permeability in response to activation of protein kinase C by phorbol esters. This response is accompanied by reorganization of the actin cytoskeleton and the formation of paracellular gaps. These studies suggest that Verge functions as a dynamic regulator of endothelial cell signaling and vascular function.

Key words: immediate early gene; IEG; endothelial cell; vascular permeability; seizure; ischemia; middle cerebral artery occlusion; MCAO; stroke model; electrical cell-substrate impedance sensing; ECIS; transendothelial resistance; TER; protein kinase C; PKC; fibroblast growth factor 2; FGF2; tumor necrosis factor ; TNF-; vascular endothelial growth factor; VEGF; hepatocyte growth factor; HGF; angiopoietin 1; Ang-1; angiopoietin 2; Ang-2

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Received Sep 17, 2003; revised March 15, 2004; accepted March 17, 2004.

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