Abstract
Little is known regarding the interplays between the mechanical and molecular bases for vein graft restenosis. We elucidated the stenosis initiation using a high-frequency ultrasonic (HFU) echogenicity platform and estimated the endothelium yield stress from von-Mises stress computation to predict the damage locations in living rats over time. The venous-arterial transition induced the molecular cascades for autophagy and apoptosis in venous endothelial cells (ECs) to cause neointimal hyperplasia, which correlated with the high echogenicity in HFU images and the large mechanical stress that exceeded the yield strength. The ex vivo perfusion of arterial laminar shear stress to isolated veins further confirmed the correlation. EC damage can be rescued by inhibiting autophagy formation using 3-methyladenine (3-MA). Pretreatment of veins with 3-MA prior to grafting reduced the pathological increases of echogenicity and neointima formation in rats. Therefore, this platform provides non-invasive temporal spatial measurement and prediction of restenosis after venous-arterial transition as well as monitoring the progression of the treatments.
Highlights
Vein graft bypass surgery is a frequently used clinical procedure for vascular reconstruction in treating cardiovascular diseases
Apoptosis analyses indicated the induction of endothelial cells (ECs) death in carotid vessels (CAV) (Fig. 1C, white arrowhead), but not in carotid arterial-arterial (CAA), as demonstrated by positively stained cells following terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) in the neointima near the lumen
Excessive autophagy formation was significantly induced in ECs of CAV in comparison to CAA, as indicated by the positive staining of intracellular microtubule-associated protein 1A/1B-light chain 3 (LC3) in neointima (Fig. 1D) and the decrease in p62 (Fig. 1E)
Summary
Vein graft bypass surgery is a frequently used clinical procedure for vascular reconstruction in treating cardiovascular diseases. Autophagy is an evolutionarily conserved process to degrade damaged organelles within the double-membrane vacuoles inside lysosomes[10] General stresses, such as starvation and bacterial infection, induce autophagy flux which protects ECs against injury by removing deleterious materials[11]. Little is known about the interrelations among autophagy, endothelial damage, and inflammatory responses in the pathological progression of vein graft disease. Understanding the dynamics of cellular mechanical responses for autophagy formation induced by venous-to-arterial flow alteration in venous ECs is critical for the management of vein graft diseases. Inhibition of excessive autophagy formation prevents the pathological initiation of vein graft failure. These results allow for the prediction of the mechanical responses in grafted veins and provide guidance for rational treatments
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