Graft-Induced Reprogramming Under Arterial Hemodynamic Stress is Associated with a Shared Proteomic Phenotype in Arterial and Venous Conduits Following Coronary Artery Bypass Grafting

Abstract

BackgroundAutologous venous conduits remain the mainstay of coronary artery bypass grafting (CABG); however, their long-term patency is limited by adverse vascular remodeling. While arterial and venous grafts undergo structural and molecular adaptation to arterial hemodynamics, the mechanisms underlying successful adaptation remain poorly characterized owing to the scarcity of functioning human graft tissues. MethodsWe analyzed bypass grafts explanted en bloc during orthotopic heart transplantation, comprising patent vein grafts (VGP, n=19), occluded vein grafts (VGO, n=9), and patent arterial grafts (AGP, n=13), alongside freshly harvested controls (vein, n=23; artery, n=11). Quantitative histomorphometry, label-free LC-MS/MS proteomics, pathway analysis, and immunohistochemistry were performed. ResultsWhile patent arterial and venous grafts exhibited medial elastin reinforcement, adventitial neovascularization, and organized intimal remodeling, occluded vein grafts demonstrated elastic layer disruption, medial degeneration, and collagen-dense fibrosis. Proteomic analysis revealed a convergent adaptive signature in patent grafts enriched for RNA metabolism, protein synthesis, cytoskeletal dynamics, and extracellular matrix organization, with shared activation of NR4A3, STAT1, and EGFR signaling. Vein-specific adaptation involved SRC-PTGES activation with concomitant STAT3 suppression, whereas arterial grafts engaged IGF1-RUNX2-associated proliferative programs. Failed venous grafts exhibited angiotensin-driven fibroinflammatory remodeling. Endothelial nitric oxide synthase expression was markedly upregulated in the luminal endothelium and adventitial neovessels of patent grafts. ConclusionsDespite distinct vascular origins, arterial and venous grafts converged toward a shared adaptive phenotype characterized by structural maturation and vasoprotective signaling. Targeting common adaptive pathways--including NR4A3, STAT1, EGFR, and adventitial eNOS--may offer therapeutic strategies to enhance long-term graft durability. WHAT ARE THE CLINICAL IMPLICATIONS?This study provides human tissue-based evidence that patent coronary bypass grafts share a common adaptive remodeling program, irrespective of whether the conduit is arterial or venous. Rather than simple venous "arterialization," successful grafts converged on a phenotype characterized by coordinated biosynthetic activity, structural maturation, and vasoprotective signaling, whereas occluded vein grafts exhibited a distinct angiotensin-driven fibroinflammatory remodeling program. Importantly, patent grafts demonstrated conserved upregulation of NR4A3, STAT1, EGFR, and endothelial nitric oxide synthase (eNOS) in both luminal and adventitial endothelial compartments, identifying molecular features that distinguish adaptive from maladaptive remodeling in humans. These findings are clinically relevant because they highlight shared, potentially targetable pathways that may support graft durability across conduit types and provide mechanistic support for surgical strategies that preserve perivascular adipose tissue during vein harvesting. Moreover, the association of graft failure with angiotensin-centered extracellular matrix remodeling suggests a modifiable biological axis that warrants further investigation. Together, this work establishes a human molecular framework for graft adaptation that may inform future biomarker development, therapeutic targeting, and precision strategies aimed at improving outcomes after coronary artery bypass grafting.