Evaluation of Venous Stenosis Angioplasty in a Murine Arteriovenous Fistula Model

Abstract

Purpose: To develop a clinically relevant model of percutaneous transluminal angioplasty (PTA) of venous stenosis in mice with arteriovenous fistula (AVF); to test the hypothesis that there is increased wall shear stress (WSS) after PTA; and to histologically characterize the vessels.Materials and Methods: Thirteen C57BL/6J male mice, 6-8 weeks old, underwent partial nephrectomy to create chronic kidney disease. Twenty-eight days later, an AVF was created from the right external jugular vein to the left carotid artery. Fourteen days later, an angioplasty or sham procedure was performed, and the mice were sacrificed 14 days later for histologic evaluation to identify the cells contributing to the vascular remodeling (a-SMA, FSP-1, CD31, and CD68), proliferation (Ki-67), cell death (TUNEL), and hypoxia staining (HIF-1a). Histomorphometric analysis was performed to assess lumen area, neointimaþmedia area, and cellular density. Ultrasound was performed weekly after creation of the AVF.Results: Venous stenosis occurred 14 days after the creation of an AVF. PTA-treated vessels had significantly higher WSS; average peak systolic velocity, with increased lumen vessel area; and decreased neointima þ media area compared to sham controls. There was a significant decrease in the staining of smooth muscle cells, fibroblasts, macrophages, HIF-1a, proliferation, and apoptosis and an increase in CD31-(þ) cells. Conclusions:A clinically relevant model of PTA of venous stenosis in mice was created. PTA-treated vessels had increased lumen vessel area and WSS. The alterations in tissue markers of vascular remodeling, tissue hypoxia, proliferation, and cell death may be implications for future design of drug and device development. ABBREVIATIONSa-SMA ¼ alpha-smooth muscle cell actin, AVF ¼ arteriovenous fistula, FSP-1 ¼ fibroblast-specific protein-1, HIF-1a ¼ hypoxia inducible factor-1 alpha, PTA ¼ percutaneous transluminal angioplasty, PV ¼ peak velocity, VNH ¼ venous neointimal hyperplasia, VVG ¼ Verhoeff-Van Gieson, WSS ¼ wall shear stress In 2015, more than 500,000 patients in the United States had end-stage renal disease (1). Arteriovenous fistula (AVF) is the preferred vascular access for hemodialysis, but the primary patency rates of AVF at 1 year and 2 years are 60% and 51%, respectively, as reported in several studies (2,3). Venous stenosis is one of the main reasons for AVF failure (4-6) and is treated with percutaneous transluminal angioplasty (PTA) (2,6), but the primary patency rate of PTA at 6, 12, and 24 months is 61%, 42%, and 35%, respectively (7).

A Novel Model of Balloon Angioplasty Injury in Rat Arteriovenous Fistula

“…Thus, inflammatory cells may also contribute to the greater intimal hyperplasia formation following angioplasty. In contrast to our findings, Cai et al [24] reported a significant reduction in intimal plus medial area, along with decreased α-SMA and CD68 expressions 14 days following percutaneous transluminal angioplasty in a murine model. Moreover, there is a recent study from Cai et al [25] demonstrating sex differences in treatment response to angioplasty in a murine AVF model.…”

“…The important role of collagen density in vascular remodeling following angioplasty has been previously reported to be associated with constrictive remodeling and restenosis [30]. Consistent with a previous report from Cai et al [24], in the present study, we have observed a significant increase of collagen expression in both AVFartery and vein in the angioplasty group compared to the control at 35 days post-AVF creation (Fig. 7).…”

Adventitial delivery of nanoparticles encapsulated with 1α, 25-dihydroxyvitamin D3 attenuates restenosis in a murine angioplasty model

“…Percutaneous transluminal angioplasty (PTA) is the first line treatment for malfunctioning AVF caused by vascular stenosis 2 . After PTA, AVF restenosis develops due to restenosis caused by venous neointimal hyperplasia (VNH) resulting in poor patency 3 , 4 . As a consequence, therapeutic measures are needed to improve AVF patency following PTA.…”

“…It is known that the normal endothelium expresses Ier3 10 , but the expression in stenotic endothelial cells from human AVFs is unknown. The gene and protein expression of IER3 was determined in outflow veins removed from mouse model of PTA 4 . We decreased Ier3 gene expression using 1,25 NP and the changes in VNH/VS were determined using histomorphometric analysis, immunohistologic changes, with hemodynamic changes assessed with Doppler ultrasound, and gene expression 4 .…”

“…The gene and protein expression of IER3 was determined in outflow veins removed from mouse model of PTA 4 . We decreased Ier3 gene expression using 1,25 NP and the changes in VNH/VS were determined using histomorphometric analysis, immunohistologic changes, with hemodynamic changes assessed with Doppler ultrasound, and gene expression 4 . Finally, we performed unbiased whole transcriptomic RNA sequencing with differential gene expression analysis on outflow veins after PTA treated with 1,25 NP compared to controls 11 .…”