MMP-9 Deletion Attenuates Arteriovenous Fistula Neointima through Reduced Perioperative Vascular Inflammation
<p>Neointima formation in the venous outflow tract of arteriovenous fistula (AVF). (<b>A</b>) Wild-type (WT) mice underwent 5/6 nephrectomy for chronic kidney disease (CKD) induction, followed by AVF creation four weeks later. Grossly, neointima formation was observed at proximal AVF venous segment. (<b>B</b>) Histologically, the initial 600 μm venous outflow tract was divided into five 100 μm thick segments as illustrated in (<b>A</b>), scale bar = 100 μm. After elastin staining, neointima at each segment was examined, which was found to enlarge gradually after AVF creation. **** <span class="html-italic">p</span> < 0.0001. Data presented as mean ± SEM and analyzed using one-way analysis of variance (ANOVA) followed by Bonferroni post hoc analysis; <span class="html-italic">n</span> = 6–7 in each group. AVF, arteriovenous fistula; CKD, chronic kidney disease; 2/3 Nx, 2/3 nephrectomy; UNx, uninephrectomy; WT, wild-type.</p> "> Figure 2
<p>Vascular inflammation and increased matrix metalloproteinase 9 (MMP-9) expression in AVF venous segment. (<b>A</b>) RNA-seq data analysis revealed four out of the top 10 enriched gene ontology terms were related to inflammation. In wild-type (WT) AVF compared to contralateral veins sampled 1-week post AV fistula creation. *** <span class="html-italic">p adjust</span> < 0.001 (<b>B</b>) The expression of multiple proinflammatory genes, including chemokines and cytokines, was also elevated (<span class="html-italic">n</span> = 3 in each group). (<b>C</b>,<b>D</b>) Using immunohistochemical staining, MMP-9(+) cells in neointima lesions increased significantly after AV fistula surgery, scale bar = 50 μm. (<span class="html-italic">n</span> = 6–7 in each time point). (<b>E</b>) MMP-9 mRNA expression was upregulated at the early perioperative phase as well. (<span class="html-italic">n</span> = 6–7 in each time point). * <span class="html-italic">p</span> < 0.05, ** <span class="html-italic">p</span> < 0.01, **** <span class="html-italic">p</span> < 0.0001. Data presented as mean ± SEM and analyzed by one-way analysis of variance (ANOVA) followed by Bonferroni post hoc analysis. CTL, control; DEG, differentially expressed genes; GO, gene ontology.</p> "> Figure 3
<p>Matrix metalloproteinase 9 (MMP-9) knockout attenuated neointima formation and increased lumen size in arteriovenous (AV) fistula venous segment. (<b>A</b>) AV fistula was created in both wild-type (WT) and MMP-9<sup>−/−</sup> mice to examine the influence on AV fistula. (<b>B</b>,<b>C</b>) Chronic kidney disease was successfully induced in both WT and MMP-9<sup>−/−</sup> mice with significantly elevated serum blood urea nitrogen (BUN) and creatinine. (<b>D</b>) Morphometric analysis was done after elastin staining, scale bar = 100 μm. (<b>E</b>) Neointima size decreased and (<b>F</b>) lumen area enlarged after MMP-9 knockout (<span class="html-italic">p</span> = 0.0013 and 0.0116, respectively). (<b>G</b>) Internal elastic lamina (IEL) perimeter was not significantly different between WT and MMP-9<sup>−/−</sup> mice. (<b>H</b>) IEL structure was examined under high magnification, and loose structure was found in both WT and MMP-9<sup>−/−</sup> mice AV fistula venous segment, scale bar = 50 μm. No visible detrimental effect was detected after MMP-9 knockout. * <span class="html-italic">p</span> < 0.05, ** <span class="html-italic">p</span> < 0.01. Data presented as mean ± SEM. Data analyzed by Student’s <span class="html-italic">t</span>-test one-way, <span class="html-italic">n</span> = 6–7 in each group.</p> "> Figure 3 Cont.
<p>Matrix metalloproteinase 9 (MMP-9) knockout attenuated neointima formation and increased lumen size in arteriovenous (AV) fistula venous segment. (<b>A</b>) AV fistula was created in both wild-type (WT) and MMP-9<sup>−/−</sup> mice to examine the influence on AV fistula. (<b>B</b>,<b>C</b>) Chronic kidney disease was successfully induced in both WT and MMP-9<sup>−/−</sup> mice with significantly elevated serum blood urea nitrogen (BUN) and creatinine. (<b>D</b>) Morphometric analysis was done after elastin staining, scale bar = 100 μm. (<b>E</b>) Neointima size decreased and (<b>F</b>) lumen area enlarged after MMP-9 knockout (<span class="html-italic">p</span> = 0.0013 and 0.0116, respectively). (<b>G</b>) Internal elastic lamina (IEL) perimeter was not significantly different between WT and MMP-9<sup>−/−</sup> mice. (<b>H</b>) IEL structure was examined under high magnification, and loose structure was found in both WT and MMP-9<sup>−/−</sup> mice AV fistula venous segment, scale bar = 50 μm. No visible detrimental effect was detected after MMP-9 knockout. * <span class="html-italic">p</span> < 0.05, ** <span class="html-italic">p</span> < 0.01. Data presented as mean ± SEM. Data analyzed by Student’s <span class="html-italic">t</span>-test one-way, <span class="html-italic">n</span> = 6–7 in each group.</p> "> Figure 4
<p>Matrix metalloproteinase 9 (MMP-9) knockout reduced α-smooth muscle actin (α-SMA) antibody and Picro Sirius stained area, and CD45(+) and Mac2(+) cells in neointima of AV fistula venous segment. (<b>A</b>) α-SMA(+) cells were the major cellular component within neointima. (<b>B</b>) The α-SMA(+) area ratio in neointima reduced after MMP-9 knockout (<span class="html-italic">p</span> < 0.0001). (<b>C</b>) Extracellular component of neointima was assessed with Picro Sirius Red staining. (<b>D</b>) The Picro Sirius Red(+) area ratio within neointima decreased in MMP-9<sup>−/−</sup> mice (<span class="html-italic">p</span> < 0.0001). (<b>E</b>) Leukocyte infiltration within neointima was determined by CD45 immunofluorescence. (<b>F</b>) MMP-9 deletion decreased CD45(+) cells/HPF in neointima (<span class="html-italic">p</span> < 0.0001). (<b>G</b>) Macrophages in the neointima was examined by Mac2 immunofluorescence. (<b>H</b>) The number of Mac2(+) cells/HPF decreased in MMP-9<sup>−/−</sup> mice (<span class="html-italic">p</span> = 0.0011). White arrows indicated positively stained cells. ** <span class="html-italic">p</span> < 0.01, **** <span class="html-italic">p</span> < 0.0001. Data presented as mean ± SEM. Data analyzed by Student’s <span class="html-italic">t</span>-test one-way, <span class="html-italic">n</span> = 6–7 in each group. HPF, high power field.</p> "> Figure 5
<p>Genome-wide mRNA expression difference of WT and MMP-9<sup>−/−</sup> mice AV fistulas. (<b>A</b>) Gene set enrichment analysis (GSEA) with Hallmark gene sets was performed to analyze the differentially expressed genes between WT and MMP-9<sup>−/−</sup> mice. Significantly enriched pathways in different categories are visualized using bubble plots of normalized enrichment score (NES) for different comparisons, including WT AVF vs. WT CTL and MMP9 AVF vs. WT AVF, and the size of each bubble is proportional to the number of core genes within the pathway. Only pathways with FDR < 0.25 were included. TNFA_SIGNALING_VIA_NFKB was positively enriched in WT AVF vs. WT CTL, but negatively enriched in MMP9 AVF vs. WT AVF. (<b>B</b>) GSEA enrichment plots of immune-related pathways in MMP-9<sup>−/−</sup> AVF vs. WT AVF. (<b>C</b>) Leading-edge analysis of six immune-related pathways. (<b>D</b>) The normalized expression value of these 14 key driver genes were expressed in heatmap, <span class="html-italic">n</span> = 3 in each group. Expression of inflammation-related genes usually associated with AV fistula stenosis such as (<b>E</b>) TNF-α, (<b>F</b>) IL-6, (<b>G</b>) MCP-1, (<b>H</b>) ICAM-1, and (<b>I</b>) VCAM-1, were examined by qPCR, <span class="html-italic">n</span> = 6–7 in each group. * <span class="html-italic">p</span> < 0.05, ** <span class="html-italic">p</span> < 0.01, **** <span class="html-italic">p</span> < 0.0001. Data presented as mean ± SEM. Data analyzed by one-way analysis of variance (ANOVA) followed by Bonferroni post hoc analysis. ICAM-1, intercellular adhesion molecule 1; IL-6, interleukin 6; MCP-1, monocyte chemoattractant protein 1; NES, normalized enrichment score; NFKB, nuclear factor kappa-light-chain-enhancer of activated B cells; TNFA and TNF-α, tumor necrosis factor-α; VCAM-1, vascular cell adhesion molecule 1.</p> "> Figure 6
<p>MMP-2 mRNA expression in AV fistula venous segment. (<b>A</b>) MMP-2 mRNA expression elevated after AV fistula creation comparing to contralateral veins sampled at 1 week, 2 weeks, and 4 weeks after AV fistula creation and the peak was at 2 weeks (<span class="html-italic">n</span> = 6~7 in each time point). (<b>B,C</b>) The deletion of MMP-9 did not make compensatory elevation of MMP-2 at 1-week and 4-weeks post AVF creation. (<span class="html-italic">n</span> = 6–7 in each group). * <span class="html-italic">p</span> < 0.05, **** <span class="html-italic">p</span> < 0.0001. Data presented as mean ± SEM and analyzed by one-way ANOVA followed by Bonferroni post hoc analysis for multiple comparison and Student’s <span class="html-italic">t</span>-test for comparison of two.</p> "> Figure 7
<p>Matrix metalloproteinase 9 (MMP-9) knockout downregulated CD44 and RAC-alpha serine/threonine-protein kinase (Akt) and extracellular signal-regulated kinases (ERK) phosphorylation in arteriovenous (AV) fistula venous segment. (<b>A</b>) Western blotting was done for evaluating the protein expression in AV fistula venous segment. (<b>B</b>) One-week post AV fistula creation, CD44 expression was increased in wild-type (WT) mice, which was reversed by MMP-9 knockout. (<b>C</b>) Akt phosphorylation was also increased after AV fistula creation and attenuated by MMP-9 knockout. (<b>D</b>) Phospho-ERK level was significantly decreased in MMP-9<sup>−/−</sup> mice. *** <span class="html-italic">p</span> < 0.001, **** <span class="html-italic">p</span> < 0.0001. Data presented as mean ± SEM. Data analyzed by one-way analysis of variance (ANOVA) followed by Bonferroni post hoc analysis, <span class="html-italic">n</span> = 6 in each group. CTL, control.</p> "> Figure 8
<p>Mouse vascular smooth muscle cell line (MOVAS) was used for in vitro study. (<b>A</b>) MCP-1 and IL-6 mRNA expression was assessed by qPCR. The influence of matrix metalloproteinase 9 (MMP-9) on MOVAS migration was assessed using (<b>B</b>,<b>C</b>) wound healing and (<b>D</b>,<b>E</b>) transwell migration assays. * <span class="html-italic">p</span> < 0.05, ** <span class="html-italic">p</span>< 0.01, *** <span class="html-italic">p</span> < 0.001, **** <span class="html-italic">p</span> < 0.0001. Data presented as mean ± SEM. Data analyzed by one-way analysis of variance (ANOVA) followed by Bonferroni post hoc analysis, <span class="html-italic">n</span> = 6 in each group.</p> ">
Abstract
:1. Introduction
2. Results
2.1. Neointima Increases Progressively in the AV Fistula Venous Segment of Wild-Type (WT) Mice
2.2. Vascular Inflammation Was Detected in the Early Perioperative Phase of AV Fistula
2.3. MMP-9 Expression Elevates Significantly during the Perioperative Period after AV Fistula Creation
2.4. MMP-9 Knockout Does Not Have Any Detrimental Influence on AVF Venous Segment OR, but Attenuates Neointimal Hyperplasia and Increases Lumen Area
2.5. MMP-9 Knockout Significantly Diminished α-Smooth Muscle Actin (α-SMA) and Collagen Content in Neointima
2.6. MMP-9 Knockout Reduced CD45(+) and Mac2(+) Cells within Neointima
2.7. MMP-9 Knockout Downregulates Perioperative Inflammation in AV Fistula
2.8. MMP-2 Expression in AV Fistula Venous Segment Was Not Significantly Altered in MMP-9 Knockout Mice
2.9. MMP-9 Knockout Downregulated CD44 and RAC-Alpha Serine/Threonine-Protein Kinase (Akt) and Extracellular Signal-Regulated Kinase (ERK) Phosphorylation in AV Fistula Venous Segment
2.10. MMP-9 Increases MCP-1 and IL-6 Expression and Migration in VSMCs
3. Discussion
4. Materials and Methods
4.1. Animal Study
4.2. Tissue Harvesting and Processing
4.3. Measurement of Serum BUN and Creatinine
4.4. Morphometric Analysis
4.5. Collagen Quantification
4.6. Immunofluorescence and Immunohistochemical Staining
4.7. RNA Extraction and Quantitative PCR Analysis
4.8. RNA Sequencing, Differential Gene Expression and GSEA
4.9. Western Blotting
4.10. Cell Culture
4.11. Cell Migration Assay
4.12. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Shih, Y.-C.; Chen, P.-Y.; Ko, T.-M.; Huang, P.-H.; Ma, H.; Tarng, D.-C. MMP-9 Deletion Attenuates Arteriovenous Fistula Neointima through Reduced Perioperative Vascular Inflammation. Int. J. Mol. Sci. 2021, 22, 5448. https://doi.org/10.3390/ijms22115448
Shih Y-C, Chen P-Y, Ko T-M, Huang P-H, Ma H, Tarng D-C. MMP-9 Deletion Attenuates Arteriovenous Fistula Neointima through Reduced Perioperative Vascular Inflammation. International Journal of Molecular Sciences. 2021; 22(11):5448. https://doi.org/10.3390/ijms22115448
Chicago/Turabian StyleShih, Yu-Chung, Po-Yuan Chen, Tai-Ming Ko, Po-Hsun Huang, Hsu Ma, and Der-Cherng Tarng. 2021. "MMP-9 Deletion Attenuates Arteriovenous Fistula Neointima through Reduced Perioperative Vascular Inflammation" International Journal of Molecular Sciences 22, no. 11: 5448. https://doi.org/10.3390/ijms22115448