1α,25-Dihydroxyvitamin D3 Encapsulated in Nanoparticles Prevents Venous Neointimal Hyperplasia and Stenosis in Porcine Arteriovenous Fistulas

Avishek K Singh; Chuanqi Cai; Sreenivasulu Kilari; Chenglei Zhao; Michael L Simeon; Edwin Takahashi; Elazer R Edelman; Hyunjoon Joon Kong; Thanila Macedo; Ravinder J Singh; Matthew W Urban; Rajiv Kumar; Sanjay Misra

doi:10.1681/ASN.2020060832

1α,25-Dihydroxyvitamin D₃ Encapsulated in Nanoparticles Prevents Venous Neointimal Hyperplasia and Stenosis in Porcine Arteriovenous Fistulas

J Am Soc Nephrol. 2021 Apr;32(4):866-885. doi: 10.1681/ASN.2020060832. Epub 2021 Feb 24.

Authors

Affiliations

¹ Department of Radiology, Vascular and Interventional Translational Laboratory, Mayo Clinic, Rochester, Minnesota.
² Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts.
³ Department of Internal Medicine, Brigham and Women's Hospital, Massachusetts, Boston, Massachusetts.
⁴ Chemical and Biomolecular Engineering, Carle Illinois College of Medicine, Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois.
⁵ Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, Minnesota.
⁶ Division of Nephrology and Hypertension, Internal Medicine, Mayo Clinic, Rochester, Minnesota.

Abstract

Background: Few therapies prevent venous neointimal hyperplasia (VNH) and venous stenosis (VS) formation in arteriovenous fistulas (AVF). Expression of the immediate early response gene X-1 (Iex-1), also known as Ier3, is associated with VNH and stenosis in murine AVFs. The study aimed to determine if local release of Ier3 long-acting inhibitor 1α,25(OH)₂D₃ from poly(lactic-co-glycolic acid) (PLGA) nanoparticles embedded in a thermosensitive Pluronic F127 hydrogel (1,25 NP) could affect VNH/VS formation in a large animal model.

Methods: Immediately after AVF creation in a porcine model of renal failure, 1,25 NP or vehicle control was injected into the adventitia space of AVF outflow veins. Scanning electron microscopy and dynamic light scattering characterized drug and control nanoparticles. Animals were sacrificed 3 and 28 days later for gene expression, immunohistologic, magnetic resonance imaging and angiography, and ultrasound analyses. Whole transcriptome RNA sequencing with differential gene expression analysis was performed on outflow veins of AVF.

Results: Encapsulation of 1α,25(OH)₂D₃ in PLGA nanoparticles formed nanoparticles of uniform size that were similar to nanoparticles without 1α,25(OH)₂D₃. The 1,25 NP-treated AVFs exhibited lower VNH/VS, Ier3 gene expression, and IER-3, MCP-1, CD68, HIF-1α, and VEGF-A immunostaining, fibrosis, and proliferation. Blood flow and lumen area increased significantly, whereas peak systolic velocity and wall shear stress decreased. Treatment increased Young's modulus and correlated with histologic assessment of fibrosis and with no evidence of vascular calcification. RNA sequencing analysis showed changes in the expression of genes associated with inflammatory, TGFβ1, and apoptotic pathways.

Conclusions: Local release of 1,25 NP improves AVF flow and hemodynamics, and reduces stenosis in association with reduction in inflammation, apoptosis, and fibrosis in a porcine model of arteriovenous fistula.

Keywords: arteriovenous fistula; drug delivery; restenosis; shear stress; vascular access.

Abstract

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