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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\u2010cell RNA sequencing are used to explore the cellular changes during AVF remodeling in human and mouse. Lymphatic network, facilitated by a group of\n                    <jats:italic>Pi16<\/jats:italic>\n                    <jats:sup>+<\/jats:sup>\n                    <jats:italic>Vegfc<\/jats:italic>\n                    <jats:sup>+<\/jats:sup>\n                    fibro\u2010progenitors, 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)\u2010C 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\u2010nephrectomy mouse AVFs is normalized, which alleviated local inflammation and neointima formation. Considering that the hyperphosphatemia is a common metabolic disorder for pre\u2010dialysis CKD patients, this study provides a novel immunoregulation strategy for AVFs under CKD condition, as suppressing BACE2\u2010mediated VEGFR3 cleavage to recover a functionally competent lymphatic network is a potential target.\n                  <\/jats:p>","DOI":"10.1002\/advs.202509632","type":"journal-article","created":{"date-parts":[[2025,8,30]],"date-time":"2025-08-30T09:33:07Z","timestamp":1756546387000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["BACE2\u2010Induced Aberrant Lymphatic Network Aggravates the Local Inflammation in Arteriovenous Fistulas With Hyperphosphatemia"],"prefix":"10.1002","volume":"12","author":[{"given":"Kai","family":"Chen","sequence":"first","affiliation":[{"name":"Departments of Cardiology the First Affiliated Hospital Zhejiang University School of Medicine Hangzhou 310003 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