Phosphoinositide-dependent signaling in arteriovenous fistula remodeling and failure: From pathophysiology to emerging therapeutic targets.

Arteriovenous fistula (AVF) is the preferred vascular access for maintenance hemodialysis because of its superior long-term patency and lower infection risk compared with prosthetic grafts and central venous catheters. Nevertheless, AVF dysfunction remains a major clinical challenge, as many fistulas fail to mature adequately or progressively develop stenosis and thrombosis. Increasing evidence suggests that AVF failure is not merely a technical complication, but the result of maladaptive vascular remodeling triggered by abrupt exposure of the venous wall to arterial hemodynamics. Endothelial dysfunction, disturbed shear stress responses, neointimal hyperplasia, extracellular matrix accumulation, inflammation, and vascular smooth muscle cell activation all contribute to this process. Among the signaling pathways implicated in vascular remodeling, phosphoinositide-dependent signaling has emerged as a potentially important regulatory system. In particular, the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) pathway integrates hemodynamic and inflammatory stimuli into programs controlling proliferation, migration, survival, and matrix remodeling. Beyond canonical PI3K signaling, upstream phosphoinositide kinases, including type I phosphatidylinositol-4-phosphate 5-kinases (PIP5Ks) and type II phosphatidylinositol-5-phosphate 4-kinases (PIP4Ks), may regulate membrane organization, cytoskeletal dynamics, mechanotransduction, and stress-responsive signaling during AVF adaptation. This review summarizes the mechanisms underlying early and late AVF failure and discusses how phosphoinositide signaling pathways may influence vascular remodeling in the fistula environment. Because direct experimental evidence on phosphoinositide involvement in AVF tissue is still lacking, the framework proposed here is deliberately presented as a hypothesis-driven, mechanistically motivated model rather than a confirmed one. Finally, the translational potential of targeting phosphoinositide metabolism as a strategy to prevent maladaptive remodeling and improve AVF outcomes is explored.