Dual Function for Mature Vascular Smooth Muscle Cells During Arteriovenous Fistula Remodeling

Abstract

Background The arteriovenous fistula ( AVF ) is the preferred form of hemodialysis access for patients with chronic kidney disease. However, AVF s are associated with significant problems including high incidence of both early and late failures, usually attributed to inadequate venous arterialization and neointimal hyperplasia, respectively. Understanding the cellular basis of venous remodeling in the setting of AVF could provide targets for improving AVF patency rates. Methods and Results A novel vascular smooth muscle cell ( VSMC ) lineage tracing reporter mouse, Myh11‐Cre/ ERT 2‐ mTmG , was used to track mature VSMC s in a clinically relevant AVF mouse model created by a jugular vein branch end to carotid artery side anastomosis. Prior to AVF surgery, differentiated medial layer VSMC s were labeled with membrane green fluorescent protein (GFP) following tamoxifen induction. Four weeks after AVF surgery, we observed medial VSMC layer thickening in the middle region of the arterialized vein branch. This thickened medial VSMC layer was solely composed of differentiated VSMC s that were GFP +/ MYH 11+/Ki67−. Extensive neointimal hyperplasia occurred in the AVF region proximal to the anastomosis site. Dedifferentiated VSMC s ( GFP +/ MYH 11−) were a major cellular component of the neointima. Examination of failed human AVF samples revealed that the processes of VSMC phenotypic modulation and intimal hyperplasia, as well as medial VSMC layer thickening, also occurred in human AVFs. Conclusions We demonstrated a dual function for mature VSMC s in AVF remodeling, with differentiated VSMC s contributing to medial wall thickening towards venous maturation and dedifferentiated VSMC s contributing to neointimal hyperplasia. These results provide valuable insights into the mechanisms underlying venous adaptations during AVF remodeling.