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. This evidence concerns the gene VEGFC and hyperphosphatemia.