Kidney Week

Abstract: FR-OR092

Temporal Activation of Notch Improves Arteriovenous Fistulas Maturation

Session Information

• Improving Vascular Access Outcomes
  October 26, 2018 | Location: 6B, San Diego Convention Center
  Abstract Time: 05:18 PM - 05:30 PM

Category: Dialysis

• 704 Dialysis: Vascular Access

Authors

• Cheng, Jizhong, Baylor College of Medicine, Houston, Texas, United States

Jizhong Cheng, MD

My long-term goal is to identify the cellular and molecular mechanisms underlying the adverse remodeling in arteriovenous fistula (AVF), the “Achilles heel” of the hemodialysis patients, and thereby facilitating the development of effective therapeutic approaches to improve AVF maturation by targeting cells and molecules involved in AVF maturation failure.

• Guo, Qunying, Baylor College of Medicine, Houston, Texas, United States

Qunying Guo,

• Huang, Fengzhang, Baylor College of Medicine, Houston, Texas, United States

Fengzhang Huang,

• Xiao, Xiaoguang, Baylor College of Medicine, Houston, Texas, United States

Xiaoguang Xiao,

• Liang, Ming, Baylor College of Medicine, Houston, Texas, United States

Ming Liang,

• Qing, Ying, Baylor College of Medicine, Houston, Texas, United States

Ying Qing,

• Mitch, William E., Baylor College of Medicine, Houston, Texas, United States

William E. Mitch,

• Truong, Luan D., The Methodist Hospital , Houston, Texas, United States

Luan D. Truong,

Background

maturation of arteriovenous fistula (AVFs) requires arterialization of the venous arm in order to sustain increased blood flow and repeated punctures. Proliferation and migration of vascular smooth muscle cells (VSMCs) are required for thickening the venous wall of AVFs. But excessive VSMC accumulation forms a neointima, ultimately, leading to AVF failure. Notch signaling determine the artery fate. Earlier, we demonstrated that Notch signaling in AVFs stimulates vascular remodeling, but complete inhibition of Notch signaling pathway block AVF arterialization. Does temporally controlled Notch activation balance AVF arterialization and neointima formation?

Methods

AVFs created in wild type (WT) and conditionally inducible, VSMC-specific Notch KO mice (RBP-Jk^VSMC-KO). Temporal Notch activation was controlled by addition of tamoxifen to KO Notch transcription factor, RBP-Jk, in VSMCs. The VSMCs were labeled and tracked; VSMC dedifferentiation, activation, and neointima formation were determined.

Results

in AVF anastomoses, VSMC contractile markers were decreased; proliferation and migration markers were markedly increased. These results document VSMC activation and dedifferentiation. In neointimas, activated Notch was present in VSMC nuclei and it induced VSMC contractile markers thereby promoting neointima formation. Pre-operative KO of RBP-Jk in VSMCs blocked expression of contractile markers causing non-arterialization of AVFs. However, when RBP-Jk was KO in VSMCs in day 10 or day 20 after AVF surgery, the VSMCs in the neointima expressed VSMC markers even without RBP-Jk expression. Consequently, arterialization of the AVF was induced and the neointima area was smaller in AVFs created in RBP-Jk^VSMC-KO mice VS. WT mice. Thus, Notch signaling is required to initiate the expression of VSMC markers. But, the signaling pathway is not required for maintaining VSMC fate. As occurred in AVF, KO or inhibition of Notch signaling suppressed PDGF-BB-induced differentiation of progenitors into VSMCs. Notch overexpression promotes PDGFRβ expression plus differentiation VSMCs from their progenitors.

Conclusion

Temporal activation of Notch improves AVF arterialization and maturation.

Funding

• NIDDK Support