A Synthetic/Fibrotic Vascular Remodeling Program Associated with Arteriovenous Fistula Maturation Failure

Background/Objectives: Arteriovenous fistula (AVF) maturation failure is associated with maladaptive vascular remodeling, but the cellular states and microenvironmental programs involved remain unclear. Methods: We integrated human single-cell, spatial, and bulk transcriptomic datasets to characterize remodeling-associated cell states and gene signatures. Regulatory network inference, computational perturbation, an external cAMP responsive element binding protein 3 like 1 (CREB3L1) -deficient mouse dataset, structural modeling, molecular docking, and TGF-β1 stimulation of human venous smooth muscle cells (SMCs) were used to investigate candidate mechanisms. Results: Single-cell analyses identified a putative SMC-associated state with ECM-related transcriptional features. Spatial analyses localized related remodeling programs in control veins and mature AVFs, while bulk analyses associated a niche-derived signature with maturation failure. Integrative regulatory network and cell–cell communication analyses further linked myofibroblast-derived TGF-β signaling to increased CREB3L1 target activity in SMCs; consistently, exogenous TGF-β1 stimulation promoted the nuclear accumulation of CREB3L1. In silico perturbation of CREB3L1 predicted suppression of the synthetic/fibrotic SMC program. Complementary transcriptional reversal screening, structural modeling, and molecular docking analyses nominated candidate compounds with potential to modulate this regulatory axis. Conclusions: Our study generates a multiscale transcriptomic map of AVF maturation failure, identifying spatial ECM-remodeling signatures that offer mechanistic insights into AVF pathogenesis.