c-Kit signaling determines neointimal hyperplasia in arteriovenous fistulae

Abstract

Skartsis N, Martinez L, Duque JC, Tabbara M, Velazquez OC, Asif A, Andreopoulos F, Salman LH, Vazquez-Padron RI. c-Kit signaling determines neointimal hyperplasia in arteriovenous fistulae. Am J Physiol Renal Physiol 307: F1095-F1104, 2014. First published September 3, 2014 doi:10.1152/ajprenal.00292.2014.-Stenosis of arteriovenous (A-V) fistulae secondary to neointimal hyperplasia (NIH) compromises dialysis delivery, which worsens patients' quality of life and increases medical costs associated with the maintenance of vascular accesses. In the present study, we evaluated the role of the receptor tyrosine kinase c-Kit in A-V fistula neointima formation. Initially, c-Kit was found in the neointima and adventitia of human brachiobasilic fistulae, whereas it was barely detectable in control veins harvested at the time of access creation. Using the rat A-V fistula model to study venous vascular remodeling, we analyzed the spatial and temporal pattern of c-Kit expression in the fistula wall. Interestingly, c-Kit immunoreactivity increased with time after anastomosis, which concurred with the accumulation of cells in the venous intima. In addition, c-Kit expression in A-V fistulae was positively altered by chronic kidney failure conditions. Both blockade of c-Kit with imatinib mesylate (Gleevec) and inhibition of stem cell factor production with a specific short hairpin RNA prevented NIH in the outflow vein of experimental fistulae. In agreement with these data, impaired c-Kit activity compromised the development of NIH in A-V fistulae created in c-Kit W/Wv mutant mice. These results suggest that targeting of the c-Kit signaling pathway may be an effective approach to prevent postoperative NIH in A-V fistulae. arteriovenous fistula; hemodialysis; neointima THE ARTERIOVENOUS (A-V) fistula is the preferred type of vascular access for hemodialysis patients (29). It achieves higher patency rates, has fewer complications than synthetic grafts (12,29,31), and has a lower risk of infections than central venous catheters (17,29). Despite its advantages, A-V fistulae frequently fail to mature or become dysfunctional after successful dialysis sessions, and this occurs primarily due to the development of neointimal hyperplasia (NIH) within the A-V fistula circuit (2, 5, 39). Stenosed A-V fistulae can sometimes be salvaged through angioplasty or surgical interventions, but these attempts often result in restenosis or additional complications (32). Therefore, there is an unmet medical need for treatments that prevent NIH and improve A-V fistula function. To this end, it is necessary to better define the factors underlying the pathological remodeling of the A-V fistula wall.A-V fistula maturation is a dynamic vascular process with multiple factors contributing to the development of NIH. These include vein configuration (22) In the present study, we investigated the role of c-Kit in the pathological remodeling of A-V fistulae. We show that activation of the c-Kit signaling pathway in adventitial and neointimal cells precedes arteri...

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

“…The existence of stem cells in the AVF wall has also been suggested by Nath and colleagues (48), who described this type of cell as a component of adventitial microvessels in rodent AVF models. Moreover, blockade of c-Kit with imatinib mesylate (Gleevec, Novartis, Basel, Switzerland) and inhibition of stem cell factor production with a specific short hairpin RNA prevented venous neointimal hyperplasia in the outflow vein in this rodent AVF model by Vazquez-Padron and colleagues (47). Thus, inhibition of c-kit may serve as a potential target for pharmacologic therapy.…”

“…Vazquez-Padron and colleagues have demonstrated in a seminal study in rodent AVF that the receptor tyrosine kinase c-Kit plays an important role in neointimal hyperplasia development (47). The presence of c-Kit may reflect progenitor cell activity in the vascular wall because this receptor tyrosine kinase is considered a marker for stem cell identification.…”

Peer Review #2 of "c-Kit modifies the inflammatory status of smooth muscle cells (v0.1)"

“…Widely recognized for its proliferative and antiapoptotic role in hematopoietic stem and progenitor cells (Bernstein et al 1991), c-Kit signaling is now known to increase endothelial permeability (Kim et al 2014;Im et al 2016), and regulate the phenotype of smooth muscle cells (SMC) in the vasculature (Wang et al 2007;Davis et al 2009). On one hand, animal models indicate that c-Kit activation by its ligand the stem cell factor (SCF) plays an important role in the development of both arterial and venous intimal hyperplasia (IH) (Hollenbeck et al 2004;Wang et al 2006;Wang et al 2007;Skartsis et al 2014). On the other hand, c-Kit expression preserves the SMC contractile phenotype (Davis et al 2009), and protects arteries from excessive atherosclerosis .…”

“…The formation of venous IH in arteriovenous fistulas (AVF) also occurs secondary to the activation of c-Kit expressing adventitial progenitors and migration of c-Kit positive myofibroblasts to the intima (Skartsis et al 2014). Both animal and human AVF demonstrate PeerJ reviewing PDF | (2016:12:15280:1:0:REVIEW 21 Apr 2017)…”

“…Manuscript to be reviewed higher numbers of c-Kit expressing SMC after surgery compared to preoperative veins, along with a transitional increase in SCF levels in animal models after AVF creation (Skartsis et al 2014).…”