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Increased vascular MMP-9 in mice lacking RNF213: moyamoya disease susceptibility gene
Shinya Sonobe1, Miki Fujimura, Kuniyasu Niizuma
1Departments of aNeurosurgery bDermatology cPediatrics, Tohoku University Graduate School of Medicine, Sendai, Japan.
Abstract:
Moyamoya disease (MMD) is a chronic occlusive cerebrovascular disease with unknown etiology. Recent genetic studies have identified RNF213 as an important susceptibility gene for MMD. To evaluate the role of RNF213 in vascular remodeling, RNF213 knockout mice (RNF213-/-) and their wild-type littermates (WT) were subjected to common carotid artery ligation to induce vascular hyperplasia. We examined the vascular expression of matrix metalloproteinase (MMP)-9, known to be increased in MMD. MMP-9 expression was significantly higher in RNF213-/- mice than in wild-type mice 1 and 7 days after common carotid artery ligation. The vascular wall was significantly thinner in RNF213-/- mice at 14 days. The increased vascular expression of MMP-9 and subsequent vascular wall thinning in RNF213-/- mice could reflect the early characteristic of MMD, consistent with the recently proposed constrictive remodeling theory.
Insights
RNF213 gene variations impact vascular remodeling. In RNF213 knockout mice, increased MMP-9 expression and thinner vessel walls mimic Moyamoya disease characteristics, suggesting a role in disease development.
Area of Science:
- Genetics
- Vascular Biology
- Neurology
Background:
- Moyamoya disease (MMD) is a chronic occlusive cerebrovascular condition with unclear causes.
- RNF213 has been identified as a key gene associated with MMD susceptibility.
- Understanding RNF213's role in vascular remodeling is crucial for MMD research.
Purpose of the Study:
- To investigate the function of RNF213 in vascular remodeling processes.
- To examine the impact of RNF213 deficiency on matrix metalloproteinase-9 (MMP-9) expression.
- To assess vascular wall changes in a mouse model lacking functional RNF213.
Main Methods:
- Utilized RNF213 knockout (RNF213-/-) and wild-type (WT) littermate mice.
- Induced vascular hyperplasia via common carotid artery ligation in both groups.
- Quantified vascular MMP-9 expression and measured vascular wall thickness at specific time points post-ligation.
Main Results:
- RNF213-/- mice exhibited significantly elevated vascular MMP-9 expression compared to WT mice at 1 and 7 days post-ligation.
- A significant thinning of the vascular wall was observed in RNF213-/- mice by day 14.
- These findings indicate a direct link between RNF213 deficiency, MMP-9 dysregulation, and altered vascular structure.
Conclusions:
- The increased MMP-9 expression and subsequent vascular wall thinning in RNF213-/- mice provide insights into early Moyamoya disease pathogenesis.
- Results support the constrictive remodeling theory of MMD development.
- RNF213 plays a critical role in maintaining vascular integrity and regulating remodeling processes relevant to MMD.
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