Yu-Chung Shih
Nationality
Taiwan
Current Position
Attending Physician / Assistant Professor
Organization
Division of Plastic and Reconstructive Surgery, Department of Surgery, Taipei Veterans General Hospital
Research Forum Session

Topic: Improving neointima formation of AVF in basic research

Abstract

Uremic patients rely on vascular access for hemodialysis, and vascular access dysfunction constitutes a major cause of morbidity in dialysis patients. Arteriovenous fistula (AVF) is the preferred vascular access due to lower complication rates, but the 1-year patency rate of AVF is only about 60%. The cause of failure is predominantly secondary to neointimal formation at the anastomosis and/or the outflow veins followed by in situ thrombosis. Surgical trauma, hemodynamic shear stress, and uremia lead to local inflammation and oxidative stress, which activate the adventitial fibroblasts or media vascular smooth muscle cells to migrate to and proliferate in the intimal region. We use a mouse arterial-end-to-venous-side AVF model to simulate the flow pattern and AVF stenosis in patients. Neointima develops gradually in the venous outflow tract of AVF and reaches about 80% stenosis at 4 weeks after AVF creation. -smooth muscle actin (+) cells and collagen are the major components within neointima. In the current mouse model, the influence of chronic kidney disease (CKD) could also be evaluated by the addition of subtotal nephrectomy. CKD increases the size of neointima and the expressions of matrix metalloproteinase 2 (MMP-2), MMP-9, tumor necrosis factor-, and transforming growth factor- in venous limb of AVF. In addition, another advantage of mouse model is the availability of genetic modified mouse strains, and we explore the influence of MMP-9 in AVF by using genetic deletion mouse. The expression of MMP-9 in AVF markedly increased after creation. Genetic deletion of MMP-9 diminished the size of neointima and enlarged the lumen area by decreasing -smooth muscle actin (+) cells and collagen components within neointima. AVF mRNA sequencing data at the early perioperative stage disclosed negatively enriched inflammation-related gene sets in AVF of MMP-9 knockout mice compared to that in WT mice. The qPCR study also revealed suppression of proinflammatory genes. In summary, the mouse AVF model is a valuable tool in the investigation of pathogenesis and treatment of AVF stenosis.

Keywords: mouse model; arteriovenous fistula (AVF); neointima formation

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