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

Abstract

Vascular Early Response Gene (Verge) is an immediate early gene (IEG) that is up-regulated in endothelial cells in response to a number of stressors, including ischemic stroke. Endothelial cell lines that stably express Verge show enhanced permeability. Increased Verge expression has also been associated with blood brain barrier breakdown. In this study we investigated the role of Verge in ischemic injury induced by middle cerebral artery occlusion (MCAO) in both Verge knockout (KO) and wild type (WT) mice. Verge KO mice had significantly less cerebral edema formation after MCAO compared to WT mice. However, stroke outcome (infarct size and neurological deficit scores) evaluated at either 24 or 72 hours after stroke showed no differences between the two genotypes. Verge deletion leads to decreased edema formation after ischemia; however acute stroke outcomes were unchanged.

Knockout of vascular early response gene worsens chronic stroke outcomes in neonatal mice

“…Firstly, acute and subacute stroke outcomes, both histological (infarct) and behavioral (corner turning preference) were not affected by Verge deletion. This is consistent with our previous study in adult animals (Liu et al, 2012c). However, loss of Verge led to significant differences in chronic outcome after an ischemic injury, suggesting that Verge signaling is important in stroke recovery.…”

“…A previous study examined the role of Verge in experimental stroke induced by 90 min middle cerebral artery occlusion (MCAO) in adult mice and found loss of Verge did not affect acute stroke outcomes (i.e., infarct size) (Liu et al, 2012c). The lack of acute effects of Verge deletion extends to neonates as shown in this study.…”

“…Verge expression is responsive to local tissue conditions, as transient focal ischemia induced a threefold increase in Verge mRNA expression in the ischemic hemisphere. Previous work has shown that mice with Verge deletion develop normally, but exhibit reduced edema formation after experimental stroke in adulthood, an effect that was independent of infarct volumes (Liu et al, 2012c) which were equivalent in Verge KO and WT adult mice. In this study, we utilized the RVM (Vannucci and Perlman, 1997) in Verge KO and WT littermate mice to induce ischemia at post-natal day 10 (P10) to test the hypothesis that Verge activation increases angiogenesis and improves chronic recovery after neonatal stroke.…”

Apold1 deficiency associates with increased arterial thrombosis in vivo

“…Little is known about the function of Apold1 in health and disease; however, it appears to be involved in several biological processes. Loss of Apold1 reduces oedema formation in a mouse model of stroke, and angiogenesis and neurogenesis in long‐term recovery from neonatal stroke . Additionally, intense physical activity as well as psychophysical stress exposure strongly activate Apold1 expression in the heart and in the brain, and the stress‐induced increase is mediated by beta‐2 adrenergic receptors .…”

“…Experiments were performed with 11‐ to 15‐week‐old male Apold1 knockout ( Apold1 −/− ) mice and wild‐type (WT) control C57Bl6/J littermates. In the Apold1(−/−) mice, the open reading frame was replaced with a beta‐gal/neo cassette . These mice were generously provided by Dr Paul Worley and backcrossed to C57Bl6/J mice for more than 6 generations.…”