Mechanical and chemical cues synergistically promote human venous smooth muscle cell osteogenesis through integrin β1‐ERK1/2 signaling: A cell model of hemodialysis fistula calcification

Abstract

Arteriovenous fistula (AVF) is the vascular access of choice for renal replacement therapy. However, AVF is susceptible to calcification with a high prevalence of 40%–65% in chronic hemodialysis patients. Repeated needle puncture for hemodialysis cannulation results in intimal denudation of AVF. We hypothesized that exposure to blood shear stress in the medial layer promotes venous smooth muscle cell (SMC) osteogenesis. While previous studies of shear stress focused on arterial‐type SMCs, SMCs isolated from the vein had not been investigated. This study established a venous cell model of AVF using the fluid shear device, combined with a high phosphate medium to mimic the uremic milieu. Osteogenic gene expression of venous SMCs upon mechanical and chemical cues was analyzed in addition to the activated cell signaling pathways. Our findings indicated that upon shear stress and high phosphate environment, mechanical stimulation (shear stress) had an additive effect in up‐regulation of an early osteogenic marker, Runx2. We further identified that the integrin β1‐ERK1/2 signaling pathway was responsible for the molecular basis of venous SMC osteogenesis upon shear stress exposure. Mitochondrial biogenesis also took part in the early stage of this venopathy pathogenesis, evident by the up‐regulated mitochondrial transcription factor A and mitochondrial DNA polymerase γ in venous SMCs. In conclusion, synergistic effects of fluid shear stress and high phosphate induce venous SMC osteogenesis via the ERK1/2 pathway through activating the mechanosensing integrin β1 signaling. The present study identified a promising druggable target for reducing AVF calcification, which deserves further in vivo investigations.

Mechanism Analysis of Vascular Calcification Based on Fluid Dynamics

“…As the AVF intima is shed due to repeated cannulation, the media is directly exposed to the fluid shear force of the blood and is more susceptible to chemical signals (phosphate molecules), which may contribute to the venous osteogenesis. Yang et al [ 115 ] established a venous cell model of AVF using a fluid shear device combined with high phosphorus medium to simulate a uremic environment. The results showed that hydrodynamic stimulation had an additive effect on the upregulation of the osteogenic marker Runx2 in VSMCs at an early stage under shear stress and high phosphorus environment.…”