Origin of Neointimal Cells in Arteriovenous Fistulae: Bone Marrow, Artery, or the Vein Itself?

Abstract

The exact origin of the neointimal cells in arteriovenous fistulae (AVFs) has not been conclusively established. This study attempts to elucidate the anatomical source of neointimal cells in AVFs. Experimental fistulas were created in Lewis wild type (WT) and transgenic rats that constitutively expressed the Green Fluorescent Protein (GFP) in all tissues. AVFs were created by anastomosing the left renal vein to the abdominal aorta after unilateral nephrectomy. Three potential sources (bone marrow, feeding artery and the fistula vein itself) were examined. The contribution of bone marrow (BM) derived cells to the AVF neointima was examined in lethally irradiated WT rats that had been rescued with GFP BM cells. Neointimal cells in these chimeric rats were mostly GFP negative indicating the non-BM origin of those cells. Then, the contribution of arterial cells to the AVF neointima was assessed in a fistula made with a GFP aorta that had been implanted orthotopically into a WT rat. In this model, most of the neointimal cells were also GFP negative demonstrating that AVF neointimal cells are not derived from the feeding artery cells. Finally to study local resident cells contribution to the formation of neointimal lesions, a composite fistula was created by interposing a GFP vein between the renal vein and the aorta in a WT recipient rat. GFP neointimal cells were only found in the transplanted vein. This study suggests that neointimal cells originate from the local resident cells of the AVF.

New Insights into Dialysis Vascular Access: Impact of Preexisting Arterial and Venous Pathology on AVF and AVG Outcomes

“…In the absence of NO, other diffusible endothelium-derived factors, such as AngII and endothelin-1, lead to vasoconstriction, VSMC proliferation, and hypertrophic remodeling through their interaction with VSMC receptors (26). In agreement with this hypothesis, Skartsis et al (27) have shown that neointimal cells of experimental AVFs are derived from activated medial VSMCs.…”

c-Kit signaling determines neointimal hyperplasia in arteriovenous fistulae

“…The existence of stem cells in the fistula wall was recently suggested by Caplice et al (8), who described this type of cells as components of adventitial microvessels in the rat A-V fistula. A number of studies have proposed bone marrow-derived progenitor cells as the source of neointimal cells in stenotic blood vessels after arterial injury (38,44,46), but their contribution seems less pronounced in the case of venous hyperplasia, as clearly demonstrated in three independent studies (9,21,43). The present work highlights the critical role played by this pathway in A-V fistula remodeling.…”

“…The A-V fistula was created right after transduction. In parallel, four A-V fistulae were created with veins that had been transduced with a lentivirus (pLL-3.1) encoding green fluorescent protein (GFP) to assess transduction efficiency in the vascular wall using confocal microscopy (43).…”

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

“…Nearly half of the cells were green fluorescent protein positive in the neointima, suggesting that smooth muscle cells migrate from the carotid artery to the jugular vein in AVFs created in these mice (24). However, another recent study has shown contradictory results and suggests that neointimal cells are derived from local resident cells in the venous limb of the AVF (45). The issue of cells originating from the bone marrow has also been explored.…”