Complexity of PEDF multifunctional signaling in retinal development and diseases.

PEDF has neuroprotective, anti-inflammatory, anti-oxidative stress, and anti-angiogenic actions, but its multifunctional mechanisms remain unclear. We map the developmental distribution of the PEDF receptors LR, LRP6, and ATGL in naïve and Pedf-/- retinas, and define receptor-specific signaling using siRNA and pharmacological inhibition. These receptors are broadly expressed in retinoblasts and acquire cell-type-specific patterns during retinal maturation via PEDF-independent mechanisms. LR and LRP6 also colocalize at the outer limiting membrane (OLM). Functionally, PEDF activates AKT, STAT3, ERK, and p38 and suppresses β-catenin in both HUVEC and ARPE-19 cells, while mTOR activation remains receptor-independent. LR and LRP6 couple PEDF to STAT3 and β-catenin in HUVECs, whereas in ARPE-19 cells LR links PEDF to AKT/STAT3/ERK and LRP6 to AKT/β-catenin. ATGL inhibition abolishes PEDF-induced AKT/STAT3/ERK/p38 signaling in both cell types. A 17-mer PEDF mimetic (Ppx) recapitulates these effects. These findings help define a framework for PEDF pleiotropy and highlight the OLM as a therapeutic interface.