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

Abstract

Vascular early response gene (Verge) is a novel immediate early gene that is highly expressed during developmental angiogenesis and after ischemic insults in adult brain. However, the role of Verge after neonatal injury is not known. In the present study, we investigated the hypothesis that Verge contributes to vascular remodeling and tissue repair after neonatal ischemic injury. The Rice–Vanucci model (RVM) was employed to induce neonatal stroke in both Verge knockout (KO) and wild-type (WT) postnatal day 10 (P10) mice. Histological and behavioral outcomes at acute (24 h), subacute (7 days) and chronic (30 days) phases were evaluated. Angiogenesis, neurogenesis, and glial scar formation were also examined in the ischemic brain. No significant differences in outcomes were found between WT and Verge mice at 24 h or 7 days after stroke. However genetic deletion of Verge led to pronounced cystic cavitation, decreased angiogenensis and glial scar formation in the ischemic hemisphere compared to WT mice at 30 days. Verge KO mice also had significantly worse functional outcomes at 30 days which was accompanied by decreased neurogenesis and angiogenesis in the ischemic hemisphere. Our study suggests that Verge plays an important role in the induction of neurogenesis and angiogenesis after ischemia, contributes to improved tissue repair, and enhances chronic functional recovery.

Dynamic regulation of VEGF-inducible genes by an ERK-ERG-p300 transcriptional network

“…DUSP5, NRARP) regulate angiogenesis ( Fig. 9H) (Al-Greene et al, 2013;Bellou et al, 2009;Herbert et al, 2012;Iaccarino et al, 2005;Mirza et al, 2013;Moehler et al, 2008;Phng et al, 2009;Pin et al, 2012;Prahst et al, 2014;Toffoli et al, 2009;Zhou et al, 2011).…”

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 .…”

“…Apolipoprotein L domain containing protein 1 ( Apold1 ), also known as vascular early response gene, is a gene identified in endothelial cells that responds to different stimuli such as ischaemia, cytokines, growth factors and stress . Genes selectively expressed in endothelial cells could primarily determine thrombus formation .…”

Cellular diversity of the somatosensory cortical map plasticity

“…The product of the vascular early response gene (Verge or Apold1) accumulates at the periphery of endothelial cells, where it functions to regulate cell permeability by remodeling the cells' cytoskeleton, allowing substances to pass through endothelial cell layers (Regard et al, 2004). A knockout of this gene is shown to exacerbate outcomes after stroke in mice (Mirza et al, 2013). Conditions inducing its expression has been studied in various tissues, and include hypoxia, ischemia, physical activity and hypertonicity Maallem et al, 2008;Regard et al, 2004;Simonsen et al, 2010)).…”