Research Paper Volume 13, Issue 12 pp 16656—16666

Programmed death-1 mediates venous neointimal hyperplasia in humans and rats

Peng Sun1, *, , Zhiwei Wang1, *, , Weizhen Liu2,3, *, , Mingxing Li1, , Shunbo Wei1, , Yanhua Xu5, , Zhentao Qiao1, , Wang Wang2,3, , Yang Fu6, , Hualong Bai1,3, , Jing’an Li4, ,

  • 1 Department of Vascular and Endovascular Surgery, First Affiliated Hospital of Zhengzhou University, Henan, China
  • 2 Department of Physiology, Medical School of Zhengzhou University, Henan, China
  • 3 Key Vascular Physiology and Applied Research Laboratory of Zhengzhou City, Henan, China
  • 4 School of Material Science and Engineering & Henan Key Laboratory of Advanced Magnesium Alloy & Key Laboratory of Materials Processing and Mold Technology, Ministry of Education, Zhengzhou University, Henan, China
  • 5 Department of Internal Medicine, First Affiliated Hospital of Zhengzhou University, Henan, China
  • 6 Department of Gastrointestinal Surgery, First Affiliated Hospital of Zhengzhou University, Henan, China
* Equal contribution

Received: April 26, 2021       Accepted: June 4, 2021       Published: June 24, 2021
How to Cite

Copyright: © 2021 Sun et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Venous neointimal hyperplasia can be a problem after vein interventions. We hypothesized that inhibiting programmed death-1 (PD-1) can decrease venous neointimal hyperplasia in a rat inferior vena cava (IVC) patch venoplasty model. The rats were divided into four groups: the control group was only decellularized without other special treatment; the PD-1 group was injected with a single dose of humanized PD-1 antibody (4 mg/kg); the PD-1 antibody coated patches group; the BMS-1 (a PD-1 small molecular inhibitor) coated patches group (PD-1 inhibitor-1). Patches were implanted to the rat IVC and harvested on day 14 and analyzed. Immunohistochemical analysis showed PD-1-positive cells in the neointima in the human samples. There was high protein expression of PD-1 in the neointima in the rat IVC venoplasty model. PD-1 antibody injection can significantly decrease neointimal thickness (p < 0.0001). PD-1 antibody or BMS-1 was successfully conjugated to the decellularized rat thoracic artery patch by hyaluronic acid with altered morphology and reduced the water contact angle (WCA). Patches coated with humanized PD-1 antibody or BMS-1 both can also decrease neointimal hyperplasia and inflammatory cells infiltration. PD-1-positive cells are present in venous neointima in both human and rat samples. Inhibition of the PD-1 pathway may be a promising therapeutic strategy to inhibit venous neointimal hyperplasia.


BMS-1: PD-1 inhibitor-1; CD: Cluster of differentiation; DAB: 3,3N-Diaminobenzidine Tertrahydrochloride; DAPI: 4′,6-diamidino-2-phenylindole; H&E: Hematoxylin and Eosin; HRP: Horseradish Peroxidase; HA: Hyaluronic Acid; IP: Intraperitoneal; IVC: Inferior Vena Cava; PD-1: Programmed Death-1; PCNA: Proliferating Cell Nuclear Antigen; PBS: Phosphate-Buffered Saline; PD-L1: Programmed Cell Death 1 Ligand 1; SD: Sprague Dawley; SDS-PAGE: Sodium Dodecyl Sulfate-Polyacrylamide Gelelectrophoresis; TGF: Transforming Growth Factor; TA: Thoracic Aorta; WCA: Water Contact Angle; WB: Western Blot.