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. Here, FLT4 is linked to hyperphosphatemia.