ASN's Mission

ASN leads the fight to prevent, treat, and cure kidney diseases throughout the world by educating health professionals and scientists, advancing research and innovation, communicating new knowledge, and advocating for the highest quality care for patients.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on Twitter

Kidney Week

Abstract: TH-PO325

Decreased Jagged1 Expression in Vascular Smooth Muscle Cells Delays Maturation of Arteriovenous Graft

Session Information

  • Vascular Access - I
    November 07, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Dialysis

  • 704 Dialysis: Vascular Access

Authors

  • Guo, Qunying, Baylor College of Medicine, Houston, Texas, United States
  • Feng, Shaozhen, Baylor College of Medicine, Houston, Texas, United States
  • Liang, Ming, Baylor College of Medicine, Houston, Texas, United States
  • Mitch, William E., Baylor College of Medicine, Houston, Texas, United States
  • Cheng, Jizhong, Baylor College of Medicine, Houston, Texas, United States

Group or Team Name

  • Internal Medicine/Nephrology
Background

It is well-known that endothelial dysfunction promotes activation of vascular smooth muscle cell (VSMC). Whether decreased accumulation of VSMCs affects endothelial regeneration and functions in arteriovenous graft (AVG) remodeling has not been studied. We plan to identify mechanisms by which the Notch ligand, Jagged1, in VSMCs regulates EC functions in AVGs.

Methods

AVGs were created in transgenic mice bearing VSMC-specific knockout (KO) or overexpression of Jagged1. VSMC migration, EC regeneration and its barrier functions as well as AVG remodeling were evaluated.

Results

Jagged1 expression was induced in VSMCs of neointima in the AVGs. Jagged1 KO in VSMCs inhibited the accumulation of extracellular matrix as well as VSMC migration. Fewer α-SMA-positive VSMCs were found in AVGs created in Jagged1 KO mice vs. results in WT mice. Decreased VSMCs in AVGs were associated with deteriorated the EC functions. In AVGs created in transgenic mice bearing Jagged1 KO in VSMCs exhibited delayed EC regeneration and impaired EC barrier function. Barrier dysfunction of ECs increased the inflammatory cell infiltration and dysregulation of AVG arterialization. In contrast, AVGs created in mice with overexpression of Jagged1 in VSMCs exhibited improved EC regeneration plus decreased macrophage infiltration. This led to AVG remodeling and arterialization. In co-cultures of ECs and VSMCs, Jagged1 deficiency in VSMCs suppressed N-cadherin and integrin β3 expression in ECs. Inhibition of integrin β3 activation delayed EC spreading and migration. Notably, Jagged1 overexpression in VSMCs stimulated the expression of N-cadherin and integrin β3 in ECs. Jagged1-induced responses were blocked by inhibition of Notch signaling.

Conclusion

our results demonstrate that Jagged1 expression in VSMCs maintains EC barrier functions and blocks infiltration of macrophages. These responses promote remodeling and arterialization of AVGs.

Funding

  • NIDDK Support