Abstract
Arteriovenous access dysfunction is a major cause of morbidity for hemodialysis patients. The pathophysiology of arteriovenous fistula (AVF) maturation failure is associated with inflammation, impaired outward remodeling (OR) and intimal hyperplasia. RP105 is a critical physiologic regulator of TLR4 signaling in numerous cell types. In the present study, we investigated the impact of RP105 on AVF maturation, and defined cell-specific effects of RP105 on macrophages and vascular smooth muscle cells (VSMCs). Overall, RP105−/− mice displayed a 26% decrease in venous OR. The inflammatory response in RP105−/− mice was characterized by accumulation of anti-inflammatory macrophages, a 76% decrease in pro- inflammatory macrophages, a 70% reduction in T-cells and a 50% decrease in MMP-activity. In vitro, anti-inflammatory macrophages from RP105−/− mice displayed increased IL10 production, while MCP1 and IL6 levels secreted by pro-inflammatory macrophages were elevated. VSMC content in RP105−/− AVFs was markedly decreased. In vitro, RP105−/− venous VSMCs proliferation was 50% lower, whereas arterial VSMCs displayed a 50% decrease in migration, relative to WT. In conclusion, the impaired venous OR in RP105−/− mice could result from of a shift in both macrophages and VSMCs towards a regenerative phenotype, identifying a novel relationship between inflammation and VSMC function in AVF maturation.
Highlights
The placement of an arteriovenous fistula (AVF) is currently regarded as the best available option for permanent vascular access in patients requiring chronic hemodialysis
We addressed the specific role of Toll-like receptor 4 (TLR4) homologue RP105 in vascular remodeling, inflammation and vascular smooth muscle cells (VSMCs) function in a murine model of AVF failure
VSMCs play a pivotal role in AVF maturation as they contribute to thickening of the venous vessel wall and the concurrent outward remodeling
Summary
The placement of an arteriovenous fistula (AVF) is currently regarded as the best available option for permanent vascular access in patients requiring chronic hemodialysis. Due to the hierarchical importance of TLR4 in the innate immune response and its ubiquitous function, the signaling activity of this protein is firmly regulated by several regulatory molecules One such regulator is RP105 (radioprotective 105, known as CD180), a cell surface protein expressed by numerous cell types, including inflammatory cells and VSMCs21, 22. In the context of both AVF maturation and failure, numerous cell types are involved including inflammatory cells and VSMCs from both the feeding artery[10, 30] and local venous wall[31], making it a unique model to unravel specific functional consequences of RP105 on remodeling in AVF. We aimed to elucidate the role of RP105 on AVF maturation in a murine model of AVF failure by assessing cell type-specific effects of RP105 deficiency, on macrophage polarization and VSMC behavior
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