BACE2‐Induced Aberrant Lymphatic Network Aggravates the Local Inflammation in Arteriovenous Fistulas With Hyperphosphatemia

Vascular endothelial growth factor (VEGF)‐C secreted by Pi16+ fibro‐progenitors lays the foundation of lymphatic network in mouse arteriovenous fistulas (AVFs), whereas the elevated phosphate (Pi) in 5/6‐nephrectomy (Nx) mouse activates p‐ERK/p‐SP1/BACE2 pathway to generate additional soluble VEGFR‐3, which causes VEGF‐C unresponsiveness and defective lymphatic network with aggravated local inflammation in AVFs under hyperphosphatemia condition. Abstract As a widely used vascular access for hemodialysis patients, arteriovenous fistula (AVF) still faces high failure rates, in which local inflammatory response is an essential factor. In animal studies, chronic kidney disease (CKD) has been reported to aggravate local inflammation in AVFs, but the mechanisms are controversial. Here, spatial transcriptomics and single‐cell RNA sequencing are used to explore the cellular changes during AVF remodeling in human and mouse. Lymphatic network, facilitated by a group of Pi16+Vegfc+ fibro‐progenitors, is revealed as an overlooked efflux tunnel to avoid extensive inflammatory retention in AVFs. In C57BL/6 mice with 5/6 nephrectomy, the elevated phosphorus impaired AVF lymphatic network by increasing soluble VEGFR3 to blunt vascular endothelial growth factor (VEGF)‐C sensitivity in lymphatic endothelial cells (LECs), for which the increased SP1/BACE2/VEGFR3 cleavage is the underlying mechanism. By creating LEC specific BACE2 knockout mice or applying BACE2 inhibitors in the anastomotic area, the lymphatic network in 5/6‐nephrectomy mouse AVFs is normalized, which alleviated local inflammation and neointima formation. Considering that the hyperphosphatemia is a common metabolic disorder for pre‐dialysis CKD patients, this study provides a novel immunoregulation strategy for AVFs under CKD condition, as suppressing BACE2‐mediated VEGFR3 cleavage to recover a functionally competent lymphatic network is a potential target. Vascular endothelial growth factor (VEGF)-C secreted by Pi16 + fibro-progenitors lays the foundation of lymphatic network in mouse arteriovenous fistulas (AVFs), whereas the elevated phosphate (Pi) in 5/6-nephrectomy (Nx) mouse activates p-ERK/p-SP1/BACE2 pathway to generate additional soluble VEGFR-3, which causes VEGF-C unresponsiveness and defective lymphatic network with aggravated local inflammation in AVFs under hyperphosphatemia condition. Abstract As a widely used vascular access for hemodialysis patients, arteriovenous fistula (AVF) still faces high failure rates, in which local inflammatory response is an essential factor. In animal studies, chronic kidney disease (CKD) has been reported to aggravate local inflammation in AVFs, but the mechanisms are controversial. Here, spatial transcriptomics and single-cell RNA sequencing are used to explore the cellular changes during AVF remodeling in human and mouse. Lymphatic network, facilitated by a group of Pi16 + Vegfc + fibro-progenitors, is revealed as an overlooked efflux tunnel to avoid extensive inflammatory retention in AVFs. In C57BL/6 mice with 5/6 nephrectomy, the elevated phosphorus impaired AVF lymphatic network by increasing soluble VEGFR3 to blunt vascular endothelial growth factor (VEGF)-C sensitivity in lymphatic endothelial cells (LECs), for which the increased SP1/BACE2/VEGFR3 cleavage is the underlying mechanism. By creating LEC specific BACE2 knockout mice or applying BACE2 inhibitors in the anastomotic area, the lymphatic network in 5/6-nephrectomy mouse AVFs is normalized, which alleviated local inflammation and neointima formation. Considering that the hyperphosphatemia is a common metabolic disorder for pre-dialysis CKD patients, this study provides a novel immunoregulation strategy for AVFs under CKD condition, as suppressing BACE2-mediated VEGFR3 cleavage to recover a functionally competent lymphatic network is a potential target. Advanced Science, Volume 12, Issue 43, November 20, 2025.