Hypoxia and hypoxia‐inducible factors promote the development of neointimal hyperplasia in arteriovenous fistula

Abstract

Key points Patients with end‐stage renal failure need arteriovenous fistulas (AVF) to undergo dialysis. However, AVFs present a high rate of failure as a result of excessive venous thickness. Excessive venous thickness may be a consequence of surgical dissection and change in oxygen concentration within the venous wall. We show that venous cells adapt their metabolism and growth depending on oxygen concentration, and drugs targeting the hypoxic response pathway modulate this response in vitro. We used the same drugs on a mouse model of AVF and show that direct or indirect inhibition of the hypoxia‐inducible factors (HIFs) help decrease excessive venous thickness. Hypoxia and HIFs can be targets of therapeutic drugs to prevent excessive venous thickness in patients undergoing AVF surgical creation. Abstract Because the oxygen concentration changes in the venous wall, surrounding tissue and the blood during surgical creation of arteriovenous fistula (AVF), we hypothesized that hypoxia could contribute to AVF failure as a result of neointimal hyperplasia. We postulated that modulation of the hypoxia‐inducible factors (HIF) with pharmacological compounds could promote AVF maturation. Fibroblasts [normal human fibroblasts (NHF)], smooth muscle cells [human umbilical vein smooth muscle cells (HUVSMC)] and endothelial cells [human umbilical vein endothelial cells (HUVEC)], representing the three layers of the venous wall, were tested in vitro for proliferation, cell death, metabolism, reactive oxygen species production and migration after silencing of HIF1/2‐α or after treatment with deferioxamine (DFO), everolimus (Eve), metformin (Met), N‐acetyl‐l‐cysteine (NAC) and topoisomerase I (TOPO), which modulate HIF‐α stability or activity. Compounds that were considered to most probably modify intimal hyperplasia were applied locally to the vessels in a mouse model of aortocaval fistula. We showed, in vitro, that NHF and HUVSMC can adapt their metabolism and thus their growth depending on oxygen concentration, whereas HUVEC appears to be less flexible. siHIF1/2α, DFO, Eve, Met, NAC and TOPO can modulate metabolism and proliferation depending on the cell type and the oxygen concentration. In vivo, siHIF1/2α, Eve and TOPO decreased neointimal hyperplasia by 32%–50%, 7 days after treatment. Within the vascular wall, hypoxia and HIF‐1/2 mediate early failure of AVF. Local delivery of drugs targeting HIF‐1/2 could inhibit neointimal hyperplasia in a mouse model of AVF. Such compounds may be delivered during the surgical procedure for AVF creation to prevent early AVF failure.

Effect of local anti-vascular endothelial growth factor therapy to prevent the formation of stenosis in outflow vein in arteriovenous fistula

“…[ 5 , 6 ] Downstream events consist of a series of pathophysiologic responses to the previous endothelial (vascular) injury, including oxidative stress, inflammation, and EC dysfunction. [ 7 , 8 ] Caused by the upstream events mentioned above, the downstream ones lead to smooth muscle cell migration from the middle membrane to the intima hyperplasia, leading to intimal hyperplasia. [ 9 ] Therefore, it is crucial to clarify the mechanisms of the venous stenosis formation and, based on this, develop strategies to prevent or delay the failure of AVF and graft.…”

Rationale and Trial Design of MesEnchymal Stem Cell Trial in Preventing Venous Stenosis of Hemodialysis Vascular Access Arteriovenous Fistula (MEST AVF Trial)

“…Several factors have been hypothesized to cause VNH, including shear stress, inflammation, oxidative stress, hypoxic injury to the vessel wall, and mechanical injury after AVF placement (3,13,15,17,(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35). An ideal cellular therapy will be one that can be obtained in large numbers with anti-inflammatory and antiproliferative properties that can be with manufactured with good manufacturing process for use in clinical trials.…”

Molecular Insights and Novel Approaches toward Individualized Arteriovenous Fistula Care

“…Targeting the HIF pathway could be a clinical strategy to improve AVF maturation. Further supporting this idea, local delivery of HIF inhibitors such as siHIF1/2α, everolimus (Eve), and topoisomerase (TOPO), inhibits neointimal hyperplasia in a mouse model of AVF [43]. It is also plausible to hypothesize that the adaptive process following reperfusion after anastomosis exposes the vein to relatively high oxygen tension potentially affecting the outcome of AVF maturation.…”