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Abstract: TH-OR47

Roles of Matrix Metalloproteinase-2 and ETS Proto-Oncogene 1 in Rodent Arteriovenous Fistula Development

Session Information

Category: Dialysis

  • 803 Dialysis: Vascular Access

Authors

  • Northrup, Hannah M., University of Utah Health, Salt Lake City, Utah, United States
  • Shiu, Yan-Ting Elizabeth, University of Utah Health, Salt Lake City, Utah, United States
  • Tey, CS Jason, University of Utah Health, Salt Lake City, Utah, United States
  • He, Yuxia, University of Utah Health, Salt Lake City, Utah, United States
  • Jaimes, Edgar A., Memorial Sloan Kettering Cancer Center, New York, New York, United States
Background

Arteriovenous fistulas (AVFs) have high rates of maturation failure with no proven effective treatments. A few clinical studies have reported that stenotic AVFs had increased expression of matrix metalloproteinases (MMPs) when compared to native veins, and post-surgery fibrosis in newly created AVFs was positively associated with maturation failure. This study therefore examined the roles of MMP-2, which is a critical MMP in vascular remodeling, and the transcription factor ETS proto-oncogene 1 (ETS-1), which is a potent pro-fibrotic factor, in AVF maturation development.

Methods

Carotid-jugular AVFs were created in global MMP-2 homozygous knockout (MMP-2 KO) mice on C57BL/6 background, with C57BL/6 mice serving as wild-type (WT) controls. Femoral AVFs were created in global ETS-1 heterozygous knockout (ETS-1 KO) rats on Sprague-Dawley (SD) background, with SD rats serving as WT controls. AVFs and contralateral non-surgical veins were harvested at 1 and 4 weeks after AVF creation for RNA sequencing (RNA-seq), histology, and morphometry.

Results

In our mouse studies, RNA-seq data indicated drastically different transcriptional profiles between non-surgical veins and AVFs at 1 week after AVF creation. Genes regulated by MMP-2 and ETS-1 were significantly enriched in AVFs. Both MMP-2 KO and ETS-1 KO had significantly increased open lumen area of the AVF veins when compapred to WT controls. In mouse studies, the percent open lumen area of the AVF veins was significantly larger in MMP KO (39% ± 6%) vs. WT (11% ± 2%) at 1 week, as well as at 4 weeks (MMP-2 KO: 20% ± 4%, WT: 6% ± 3%) (p<0.05 for both time points). ETS-1 expression was decreased in MMP-2 KO when compapred to WT. In rat studies, the percent open lumen area of the AVF veins was significantly larger in ETS-1 KO (70% ± 9%) vs. WT (39% ± 15%) at 1 week (p=0.04) and trending larger in ETS-1 KO (52% ± 26%) vs. WT (22% ± 7%) at 4 weeks (p=0.13).

Conclusion

Our animal studies showed that inhibition of MMP-2 and ETS-1 by genetic knockout improved AVF development. Therapeutic approaches of inhibiting these molecules may enhance AVF maturation in hemodialysis patients.

Funding

  • NIDDK Support