Loss of vascular early response gene reduces edema formation after experimental stroke

The endothelial cells of the brain blood barrier (BBB) are the first line of the defense between the systemic circulation and the brain [1,2]. After stroke, changes in cell shape lead to a loosening of endothelial cell-cell contacts, impairing endothelial barrier function and increasing paracellular permeability. The subsequent development of tissue edema contributes to worsening of injury in many illnesses, including stroke [3]. Immediate early genes (IEG) are activated within minutes of stimulation and thus do not require de novo protein synthesis. They are critical in determining how gene transcription is controlled in response to extracellular signaling [4]. One of the initial genes of this class discovered was fos, which was found to be rapidly induced by growth factor treatment without the need for new protein synthesis [5]. IEGs such as c-jun and c-fos are involved in ischemic injury [6,7], and are strongly associated with downstream endothelial responses [8]. Verge is a novel IEG selectively induced in endothelial cells after ischemia or acute systemic hypertonicity, which has been associated with enhanced vascular permeability [9,10]. However, whether Verge contributes to the development of ischemic injury, or enhances stroke-induced BBB dysfunction is not clear. In this study, we used both Verge KO and C57BL6 WT littermate mice to test the hypothesis that deletion of Verge would reduce cerebral edema and improve stroke outcomes induced by MCAO.Both Verge KO (Original breeding pairs from John Hopkins University) and WT C57BL6 littermates (Charles River, Frederick, Maryland) were 10–12？weeks of age (20–25？g) when subjected to MCAO. Genotyping was performed by PCR with the following primers: F2 5′-CTCTAGCCTAGGGCAGCAAC-3′; wtR1 5′-GAGAGAGGTCGGACGTGATG-3′; LacZR 5′-GGCGATTAAGTTGGGTAACG-3′ (Regard and Worley, unpublished data). This study was conducted in accordance with NIH guidelines for the care and use of animals in research and under protocols approved by t