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 (24h), 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 24h 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.

Keywords: 5-Bromo-2′-deoxyuridine; Angiogenesis; BrdU; CD105; CV; DAPI; Ischemic stroke; KO; MCAO; Neonate; NeuN; Neurogenesis; P10; PAIS; RVM; Rice–Vanucci model; TTC; VWF; Vascular early response gene; Verge; Von Willebrand factor; WT; cresyl violet; dihydrochloride; endoglin; knockout; middle cerebral artery occlusion; neuronal nuclear antigen; perinatal arterial ischemic stroke; post-natal day 10; triphenyltetrazolium chloride; vascular early response gene; wild-type.