Anti-Vascular Endothelial Growth Factor Treatment Suppresses Early Brain Injury After Subarachnoid Hemorrhage in Mice

Abstract

The role of vascular endothelial growth factor (VEGF) in early brain injury (EBI) after subarachnoid hemorrhage (SAH) remains unclear. The aim of this study was to investigate effects of anti-VEGF therapy on EBI after SAH. C57BL/6 male mice underwent sham or filament perforation SAH modeling, and vehicle or two dosages (0.2 and 1 μg) of anti-VEGF antibody were randomly administrated by an intracerebroventricular injection. Neuroscore, brain water content, immunoglobulin G staining, and Western blotting were performed to evaluate EBI at 24-48 h. To confirm the role of VEGF, anti-VEGF receptor (VEGFR)-2 (a major receptor of VEGF) antibody was intracerebroventricularly administered and the effects on EBI were evaluated at 24 h. A higher dose, but not a lower dose, of anti-VEGF antibody significantly ameliorated post-SAH neurological impairments and brain edema at 24-48 h post-SAH. Post-SAH blood-brain barrier disruption was also inhibited by anti-VEGF antibody. The protective effects of anti-VEGF antibody were associated with the inhibition of post-SAH induction of VEGF, VEGFR-2, phosphorylated VEGFR-2, interleukin-1β and a matricellular protein tenascin-C (TNC). Anti-VEGFR-2 antibody also suppressed post-SAH neurological impairments and brain edema associated with VEGFR-2 inactivation and TNC downregulation. These findings demonstrated that VEGF causes post-SAH EBI via VEGFR-2 and TNC and that anti-VEGF therapy is effective for post-SAH EBI.

Mechanisms of Global Cerebral Edema Formation in Aneurysmal Subarachnoid Hemorrhage

“…74,75 Consistent with this hypothesis, inhibition of VEGF activity, either through antibodies directed at the molecule itself or one of its receptors (VEGFR2), significantly ameliorates blood-brain barrier disruption and cerebral edema following experimental aSAH. 76 Several other studies exploring blockade of HIF-1, the transcription factor responsible for VEGF production, demonstrate concurrent reductions in both VEGF expression and brain edema. 58,77,78 Given that a number of anti-VEGF directed therapies, such as the monoclonal antibody bevacizumab, are in clinical use, these strategies merit further exploration for the treatment of cerebral edema in aSAH.…”

Antioxidant Melatonin: Potential Functions in Improving Cerebral Autoregulation After Subarachnoid Hemorrhage

“…The structural and functional integrity of endothelial cells is essential for maintaining stable cerebral autoregulation ( Preckel et al, 1996 ; White et al, 2000 ; Ainslie et al, 2007 ; Guo et al, 2016 ). After SAH, both structural and functional integrity were damaged because of factors, such as the high concentration of ROS/RNS and inflammatory responses ( Figure 1 ) ( Kajita et al, 1998 ; Scharbrodt et al, 2009 ; Szatmari et al, 2010 ; Sabri et al, 2011 ; Qin et al, 2012 ; Liu et al, 2016 ; de Azevedo et al, 2017 ; Shekhar et al, 2017 ; Armstead et al, 2018 ). In inflammatory responses, various inflammatory pathways, such as the NF-κB pathway ( Pawlowska et al, 2018 ), NLRP3 pathway ( Li et al, 2016 ; Shao et al, 2016 ), and TLR4 pathway ( Zhang et al, 2016 ), are activated and have negative effects on the arterial endothelium after SAH.…”

The choroid plexus as a site of damage in hemorrhagic and ischemic stroke and its role in responding to injury

“…Additionally, there are multiple papers indicating a protective effect of ICV administered VEGF in ischemic stroke [97–100] suggesting that CP production of VEGF could have protective effects in stroke. However, it should be noted that Liu et al [101] recently found that ICV administration of an anti-VEGF receptor-2 antibody reduced early brain injury in a mouse SAH model.…”