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<p>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 <i>Pedf</i><sup><i>−/−</i></sup> 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.</p><p></p>

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Complexity of PEDF multifunctional signaling in retinal development and diseases

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月9日

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  • Zihao Yu,
  • Mingliang Zhang,
  • Changjie Ren,
  • Xiaomin Zhang,
  • Colin J. Barnstable,
  • Joyce Tombran-Tink,
  • Xiaorong Li

摘要

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.