Endothelial Cell TGF-β (Transforming Growth Factor-Beta) Signaling Regulates Venous Adaptive Remodeling to Improve Arteriovenous Fistula Patency

Abstract

BACKGROUND: Arteriovenous fistulae (AVF) are the gold standard for vascular access for hemodialysis. Although the vein must thicken and dilate for successful hemodialysis, excessive wall thickness leads to stenosis causing AVF failure. Since TGF-β (transforming growth factor-beta) regulates ECM (extracellular matrix) deposition and smooth muscle cell (SMC) proliferation—critical components of wall thickness—we hypothesized that disruption of TGF-β signaling prevents excessive wall thickening during venous remodeling. METHODS: A mouse aortocaval fistula model was used. SB431542—an inhibitor of TGF-β receptor I—was encapsulated in nanoparticles and applied to the AVF adventitia in C57BL/6J mice. Alternatively, AVFs were created in mice with conditional disruption of TGF-β receptors in either SMCs or endothelial cells. Doppler ultrasound was performed serially to confirm patency and to measure vessel diameters. AVFs were harvested at predetermined time points for histological and immunofluorescence analyses. RESULTS: Inhibition of TGF-β signaling with SB431542-containing nanoparticles significantly reduced p-Smad2–positive cells in the AVF wall during the early maturation phase (days 7–21) and was associated with decreased AVF wall thickness that showed both decreased collagen density and decreased SMC proliferation. SMC-specific TGF-β signaling disruption decreased collagen density but not SMC proliferation or wall thickness. Endothelial cell–specific TGF-β signaling disruption decreased both collagen density and SMC proliferation in the AVF wall and was associated with reduced wall thickness, increased outward remodeling, and improved AVF patency. CONCLUSIONS: Endothelial cell–targeted TGF-β inhibition may be a translational strategy to improve AVF patency.

Periadventitial β-aminopropionitrile-loaded nanofibers reduce fibrosis and improve arteriovenous fistula remodeling in rats

“…TGF-β, BMP, and insulin growth factor are all associated with AVF stenosis (23, 51-53). TGF-β in particular plays an important role in AVF vascular remodeling, regulating ECM deposition and VSMC proliferation (54,55). Gdf10, Tgfb3, and Igf2 were strongly downregulated with BAPN treatment along with TGF-β and insulin growth factor ECM binding proteins, Ltbp3, Ltbp4 and Igfbp5.…”

Increased expression of the P2Y 12 receptor is involved in the failure of autogenous arteriovenous fistula caused by stenosis

“…TGF-β, a multifunctional cytokine, exerts control over extracellular matrix (ECM) deposition and SMC proliferation, both of which hold pivotal roles in neointimal hyperplasia leading to AVF stenosis [ 42 , 43 , 57–64 ]. Elevated TGF-β expression within stenoses in human AVF [ 43 ], and genetic polymorphisms that express high amounts of TGF-β protein correlate with lower AVF patency [ 65 ].…”

“…TGF-β assumes a central role in kidney and vascular fibrosis and stands as a determinant for AVF functioning [ 67 ]. Additionally, TGF-β orchestrates inflammation within the remodeling AVF wall [ 42 ]. The pivotal role of inflammation in vascular remodeling and AVF maturation, with macrophages playing an essential part in AVF maturation, underscores the significance of inflammatory cells [ 68–71 ].…”

Function of TGFβ (Transforming Growth Factor-β) Receptor in the Vein Is Not in Vain

“…In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology , Taniguchi et al 1 report that targeting the TGFBR (TGFβ [transforming growth factor β] receptor) can improve AVF patency. This study disrupted the TGFβ pathway by a pharmacological agent, and by genetic cell specific deletion of TGFβ receptor in smooth muscle cells (SMCs, Tgfbr2 flx/flx / Myh11-CreER T2 ) or endothelial cells (ECs, Tgfbr1/2 flx/flx /Cdh5-CreER T2 ; Figure).…”

“…Taniguchi et al 1 identified the ECs as the key cell type in regulating venous remodeling in the AVF. Using a similar mouse AVF model, an earlier study reported that AVF formation resulted in a significant increase in the blood pressure in the vein due to its exposure to the aortic flow.…”