Hypoxia Response Element-Regulated MMP-9 Promotes Neurological Recovery via Glial Scar Degradation and Angiogenesis in Delayed Stroke

Abstract

Matrix metalloproteinase 9 (MMP-9) plays a beneficial role in the delayed phase of middle cerebral artery occlusion (MCAO). However, the mechanism is obscure. Here, we constructed hypoxia response element (HRE)-regulated MMP-9 to explore its effect on glial scars and neurogenesis in delayed ischemic stroke. Adult male Institute of Cancer Research (ICR) mice underwent MCAO and received a stereotactic injection of lentivirus carrying HRE-MMP-9 or normal saline (NS)/lentivirus-GFP 7 days after ischemia. We found that HRE-MMP-9 improved neurological outcomes, reduced ischemia-induced brain atrophy, and degraded glial scars (p < 0.05). Furthermore, HRE-MMP-9 increased the number of microvessels in the peri-infarct area (p < 0.001), which may have been due to the accumulation of endogenous endothelial progenitor cells (EPCs) in the peri-infarct area after glial scar degradation. Finally, HRE-MMP-9 increased the number of bromodeoxyuridine-positive (BrdU)/NeuN cells and the expression of PSD-95 in the peri-infarct area (p < 0.01). These changes could be blocked by vascular endothelial growth factor receptor 2 (VEGFR2) inhibitor SU5416 and MMP-9 inhibitor 2-[[(4-phenoxyphenyl)sulfonyl]methyl]-thiirane (SB-3CT). Our results provided a novel mechanism by which glial scar degradation and vascular endothelial growth factor (VEGF)/VEGFR2-dependent angiogenesis may be key procedures for neurological recovery in delayed ischemic stroke after HRE-MMP-9 treatment. Therefore, HRE-MMP-9 overexpression in the delayed ischemic brain is a promising approach for neurological recovery.

Chronic Hypoxia-Induced Microvessel Proliferation and Basal Membrane Degradation in the Bone Marrow of Rats Regulated through the IL-6/JAK2/STAT3/MMP-9 Pathway

“…Our results show that MMP-9 expression is enhanced in hypoxia. Consistent with previous studies [46,47],we observed that increased MMP-9 expression results in an elevation of MVD and BM degradation [30][31][32][33][34]. In our study, we observed an increase in MMP-9 in the CH rat bone marrow, which resulted in an increased MVD and BM degradation.…”

“…Additionally, previous studies have shown that vascular endothelial cells are produced under hypoxic conditions, which enhance microvessel proliferation. Consistent with these findings, we observed that, under hypoxia, the MVD increased because the vascular endothelial cells are produced [46][47][48][49][50].…”

Dl‐3‐N‐butylphthalide promotes angiogenesis and upregulates sonic hedgehog expression after cerebral ischemia in rats

“…CD31 + endothelial cells are used to evaluate the number of microvessels with immunostaining and are one method to detect angiogenesis. 40 To determine whether NBP promoted angiogenesis in the peri-infarct area, the number of CD31 + microvessels was examined in the ischemic perifocal region 14 days after MCAO. Immunostaining results showed that the number of CD31 + cells increased in the ischemic perifocal region of NBP-treated rats compared to that of the oil-treated rats (P < 0.05, Figure 2B).…”

Sirt3 Mediates the Inhibitory Effect of Adjudin on Astrocyte Activation and Glial Scar Formation following Ischemic Stroke

“…Furthermore, glial scar is not only a physical barrier to neurons trying to connect with vascular but also generates inhibitory molecules preventing axon regrowth (Abeysinghe et al, 2016 ). Therefore, inhibiting astrogliosis astrocytes to further reduce the glial scar is an important target for neurovascular recovery (Cai et al, 2017 ). Our results showed that adjudin could promote neurogenesis and angiogenesis following ischemic stroke which might be partly due to the reduction of glial scar area.…”