Stenosis in Mature Arteriovenous Fistulas Characterized by Contractile Smooth Muscle Cells and Versican.

INTRODUCTION

Stenosis occurs in 20% to 40% of mature arteriovenous fistulas (AVFs). Alterations of the vessel wall composition in stenosis should provide insights into its pathogenesis. However, there is a dearth of studies examining the vessel wall composition of AVF with secondary failure.

METHODS

Twenty-one AVF explants were used. Cellular (vascular smooth muscle cells [vSMCs]) and noncellular components (collagen and extracellular matrix [ECM]) were quantified using a customized machine-learning approach.

RESULTS

AVFs were explanted for aneurysms (16/21), pseudoaneurysms (2/21), or cosmetic reasons (3/21). Fifteen of the AVFs had a stenotic lesion. Proteoglycans and collagen predominated over vSMCs in the AVF wall and showed disruptions along the needle tracks. The stenotic wall showed compact collagen organization and higher expression of perlecan, versican, and versikine, and a linear correlation between versican and versikine. vSMCs in stenosis showed higher myosin heavy chain 11 (MYH11), Calponin, and smooth muscle actin (contractile and/or quiescent markers) than Ki67, a proliferative marker, without an increase in osteopontin (a secretory marker). Proliferating cells were located > 50 to 100 microns from the subendothelium.

CONCLUSION

Advanced stenosis in mature AVFs are characterized by contractile vSMC phenotype and predominated by extracellular and proteoglycan-rich remodeling raising a possibility of AVF stenotic lesions as a temporal continuum in which vSMCs initially adopt a synthetic and/or proliferative phenotype during stenosis formation and subsequently contractile phenotype as the stenosis stabilizes. Although providing potential insights into the heterogeneous response of paclitaxel-coated devices in AVF stenosis, this study underscores the need for a deeper understanding of the biology of stenosis in mature AVFs and the use of targeted therapies for specific components in AVF stenosis.