Characterization of a Model of an Arteriovenous Fistula in the Rat

Abstract

Vascular access dysfunction contributes to the mortality of patients undergoing chronic hemodialysis. The present study analyzed the changes that evolve in a femoral arteriovenous fistula in the rat. The venous segment of this model exhibited, at 1 week, activation of pro-inflammatory transcription factors and up-regulation of pro-inflammatory , proliferative , procoagulant, and profibrotic genes; and at 4 weeks, the venous segment displayed neointimal hyperplasia, smooth muscle proliferation, and thrombus formation. These changes were accompanied by endothelial (e) nitric oxide synthase (NOS) and inducible (i) NOS up-regulation. The administration of N G -nitro-L-arginine methyl ester, an inhibitor of NOS activity, increased venous neointimal hyperplasia and pro-inflammatory gene expression (monocyte chemoattractant protein؊1 and cytokine-induced neutrophil chemoattractant-1), increased systolic blood pressure, and decreased blood flow through the fistula. In another hypertensive model, the rat subtotal nephrectomy model, venous neointimal hyperplasia in the arteriovenous fistula was also exacerbated. We conclude that this arteriovenous fistula model recapitulates the salient features observed in dysfunctional, hemodialysis arteriovenous fistulas, and that venous neointimal hyperplasia is exacerbated when this model is superimposed in two different models of systemic hypertension. Since the uremic milieu contains increased amounts of asymmetric dimethylarginine , we speculate that such accumulation of this endogenous inhibitor of NOS , by virtue of its pressor or nitric oxide-depleting effects , or a combination thereof , may contribute to the limited longevity of arteriovenous fistulas used for hemodialysis.

New Insights into Dialysis Vascular Access: Molecular Targets in Arteriovenous Fistula and Arteriovenous Graft Failure and Their Potential to Improve Vascular Access Outcomes

“…The endothelium exerts its effects on vascular remodeling by secreting important vasodilatory factors, such as NO, primarily through activation of NO synthase (NOS). A seminal study by Nath and colleagues (22) in rat AVFs administered NG-nitro-L-arginine methyl ester, an inhibitor of NOS, demonstrated that NOS inhibition decreased AVF blood flow, and increased venous neointimal hyperplasia and gene expression of proinflammatory molecules. Another seminal study from Cheng and colleagues have shown that the endothelial barrier is dysfunctional after AVF creation and exacerbated in the setting of CKD, leading to increased neointimal hyperplasia development (23).…”

Novel Therapies for Hemodialysis Vascular Access Dysfunction

“…These hemodynamic characteristics likely contribute to the accelerated pace of neointimal hyperplasia in this model (8). It is less technically challenging to create an AVF in a rat compared with a mouse, but as with the mouse, the AV access blood flow parameters differ from those parameters in humans (14)(15)(16).…”

Novel Paradigms for Dialysis Vascular Access

“…In a murine model with CKD, accelerated neointimal hyperplasia was present in AVFs compared with non-CKD mice (67). In addition to porcine and murine models of CKD to study vascular access dysfunction, a rat model of CKD has also been superimposed on the rat AVF to demonstrate the damaging effect of uremia on the AVF in rat (39).…”

“…The main advantages of small animal models are that they allow for evaluation of specific pathways through specific knockout genes. The main small-animal models of dialysis access have been murine and rodents model (26,32,39,62,63). Large-animal models are advantageous because they have vessel anatomy similar to that of humans and provide the opportunity to study in detail hemodynamics and histology, but also allow for testing of experimental drug therapies and devices.…”

“…A recent study in a rodent AVF model evaluated inhibition of endothelial and inducible nitric oxide synthase (eNOS and iNOS) with N G -nitro-L-arginine methyl ester and reported that venous neointimal hyperplasia and MCP-1 were significantly elevated in the group of rodents administered N G -nitro-L-arginine methyl ester (39). On a clinical level, asymmetric dimethylarginine, an endogenous inhibitor of NOS, accumulates with progressive CKD, and high levels are associated with aggressive restenosis after angioplasty in AVF (40).…”