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Abstract: TH-OR140

Inactivation of Lysyl Oxidase in Smooth Muscle Cells Improves Arteriovenous Fistula Function in Mice

Session Information

Category: Dialysis

  • 704 Dialysis: Vascular Access

Authors

  • Vazquez-Padron, Roberto I., University of Miami, Miami, Florida, United States
  • Hernandez, Diana Rosa, University of Miami, Miami, Florida, United States
  • Martinez, Laisel, University of Miami, Miami, Florida, United States
  • Tabbara, Marwan, University of Miami, Miller School of Medicine, Miami, Florida, United States
  • Duque, Juan Camilo, University of Miami, Miami, Florida, United States
  • Salman, Loay H., Albany Medical College, Albany, New York, United States

Group or Team Name

  • Vazquez-Padron's team
Background

Over 400,000 patients in the U.S. depend on vascular access to receive hemodialysis (HD) and prolong their lives. Unfortunately, arteriovenous fistulas (AVFs), the preferred vascular access for HD, frequently fail (~40%) because venous stenosis compromises blood flow. We recently discovered that stenosis occurs due to excessive medial fibrosis and is aggravated by intimal hyperplasia. Herein, we hypothesize that it is possible to prevent AVF failure by targeting lysyl oxidase (LOX), a copper-dependent amine oxidase involved in collagen and elastin crosslinking and in the epigenetic control of gene expression in smooth muscle cells (SMCs).

Methods

We created a LOX conditional knockout mouse[Loxf/fMyh11-CreERT2] that is fertile, normal in size, and without any gross abnormalities. AVF were created by anastomosing the jugular vein to the nearby carotid artery. Mechanistic studies were performed with primary cultures of mouse venous SMC.

Results

Tamoxifen (TAM) injections significantly downregulated LOX gene expression[3 folds vs. control, p<0.01] and protein accumulation in the vasculature of conditional KO mice but not in those of control littermates[Lox+/+Myh11-CreERT2]. Inactivation of LOX in SMCs decreased immature collagen crosslinking in the aorta[1.3 ± 0.1 vs. 1.7 ± 0.1 HLNL+DHLNL/collagen], and reduced carotid pulse wave velocity[2.2 ± 0.2 vs. 2.9 ± 0.4 m/s] as determined by ultrasound microscopy. AVFs in mice with LOX-deficient SMCs showed higher distensibility and blood flow by day 21 post-surgery. Importantly, gene deletion caused aneurysms neither in the fistula nor in other parts of the vasculature. Mechanistically, we demonstrated that inhibition of LOX with BAPN increased H3K4me2 and H3K4me1 marks in the SMC genome, and specifically in the promoters of SMC contractile genes, to keep them in an open chromatin state and promote the binding of the SRF-myocardin transcription complex. We further confirmed the increased abundance of SRF in the CArG boxes of contractile gene promoters in SMCs treated with BAPN compared to the vehicle using a quantitative ChIP assay.

Conclusion

These data indicate, for the first time, the importance of LOX not only in post-operative vascular remodeling after AVF creation but also in the control of the SMC phenotype.