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Abstract
Increase of blood brain barrier (BBB) permeability after acute ischemia stroke is a predictor to intracerebral hemorrhage transformation (HT) for tissue plasminogen activator (tPA) thrombolysis and post-endovascular treatment. Previous studies showed that 2-h ischemia induced damage of BBB integrity and matrix metalloproteinase-2 (MMP-2) made major contribution to this disruption. A recent study showed that blocking β2-adrenergic receptor (β2-AR) alleviated ischemia-induced BBB injury by reducing hypoxia-inducible factor-1 alpha (HIF-1α) level. In this study, we sought to investigate the interaction of HIF-1α with MMP-2 and vascular endothelial growth factor (VEGF) in BBB injury after acute ischemia stroke. Rat suture middle cerebral artery occlusion (MCAO) model was used to mimic ischemia condition. Our results showed that ischemia produced BBB damage and MMP-2/9 upregulation was colocalized with Rhodamine-dextran leakage. Pretreatment with YC-1, a HIF-1α inhibitor, alleviated 2-h ischemia-induced BBB injury significantly accompanied by decrease of MMP-2 upregulation. In addition, YC-1 also prevented VEGF-induced BBB damage. Of note, VEGF was shown to be colocalized with neurons but not astrocytes. Taken together, BBB damage was reduced by inhibition of interaction of HIF-1α with MMP-2 and VEGF during acute cerebral ischemia. These findings provide mechanisms underlying BBB damage after acute ischemia stroke and may help reduce thrombolysis- and post-endovascular treatment-related cerebral hemorrhage.
Highlights
Damage of blood brain barrier (BBB) integrity after acute ischemia stroke is a promising target (Jin et al, 2014; Liu et al, 2016) for clinical intervention to reduce hemorrhage transformation (HT) in patients with intravenous tissue plasminogen activator or post-endovascular treatment (Leigh et al, 2016)
After incubating the brain slice with FITC-labeled DQ gelatin, compared to the non-ischemic (NI) hemisphere, there was a significant increase of gelatinolytic activity in the ischemic (I) hemisphere where dextran leakage was detected (Figure 1A) and quantitative data confirmed the ischemia-induced matrix metalloproteinase (MMP)-2/9 activity upregulation (Figure 1B)
There is no significant difference between the levels of matrix metalloproteinase-2 (MMP-2) in the non-ischemic (NI) hemisphere and similar results were observed for MMP-9 (Figure 2A)
Summary
Damage of blood brain barrier (BBB) integrity after acute ischemia stroke is a promising target (Jin et al, 2014; Liu et al, 2016) for clinical intervention to reduce hemorrhage transformation (HT) in patients with intravenous tissue plasminogen activator (tPA; Leigh et al, 2014) or post-endovascular treatment (Leigh et al, 2016). Blocking β2-adrenergic receptor (β2-AR) alleviated ischemia-induced BBB damage by reducing hypoxia-inducible factor-1 alpha (HIF-1α) level (Sun et al, 2017). It is not clear about the interaction of HIF-1α with MMP-2 in BBB damage during acute ischemia
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