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

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 beta 1-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 gamma 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 beta 1 signaling. The present study identified a promising druggable target for reducing AVF calcification, which deserves further in vivo investigations.

Automated summary

The study demonstrated that exposure to fluid shear stress and a high phosphate environment can lead to venous smooth muscle cell osteogenesis through activation of the integrin beta 1-ERK1/2 signaling pathway. Mitochondrial biogenesis also played a role in the early stage of venopathy pathogenesis. These findings suggest a potential therapeutic target for reducing AVF calcification and warrant further investigation in vivo.