Abstract: SA-OR092

CKD-induced Hedgehog/PDGFRα Signaling Activates Mesenchymal Stem Cells, Accelerating Arteriovenous Fistula Failure

Session Information

Category: Hypertension

  • 1103 Vascular Biology and Dysfunction

Authors

  • Song, Ke, 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
Background

we find that ~50% of neointima cells in failing arteriovenous fistulas (AVF), originate from vascular smooth muscle cells (VSMCs) of the arterial anastomosis. Other sources of VSMCs are unclear. One contributor is the adventitial Gli1+-mesenchymal stem cells (MSCs) that transdifferentiate into fibroblasts or VSMCs. How MSCs contribute to AVF neointimal formation in CKD mice is unknown.

Methods

in mice, we created CKD and then, AVFs in order to study how Hedgehog/PDGFRα signaling stimulates activation and differentiation of MSCs. We also examined crosstalk between MSCs and VSMCs assessed both in vivo and in vitro. This was possible because we labelled VSMCs and MSCs by using SMMHC-ERCre and Gi1-ERCre reporter mice, respectively.

Results

in AVFs, created in Gli1-CreER uremic mice, few GFP-labelled MSCs were in the neointima. Most of these MSCs were in the adventitia and they expressed fibroblast markers. Using VSMC reporter mice (SMMHC-ERCre mice), we found that VSMCs migrated into the AVF adventitia. Consequently, adventitial MSCs were able to interact with VSMCs, promoting activation and proliferation of VSMCs. What accounts for these interactions? First, we found that CKD stimulates MSCs to differentiate into either myofibroblasts or VSMCs via TGF-β1. MSCs isolated from CKD showed increased potential for differentiation into myofibroblasts with the expense of adipogenesis. Secondly, there was increased hedgehog signaling in MSCs that increased the expression of PDGFRα which is required for activation of TGF-b1 signaling. Notably, an inducible-specific KO of PDGFRα in MSCs led to reduced MSCs differentiation into adventitial fibroblasts. This process impairs VSMC activation resulting in reduced neointima area with increased AVF patency despite CKD.

Conclusion

CKD activates hedgehog/PDGFRα signaling in adventitial MSCs, promoting their differentiation into myofibroblasts or VSMCs. Interfering with the Hedgehog/PDGFRα signaling pathway in MSCs could suppress neointima formation with improvement in AFV maturation.

Funding

  • NIDDK Support