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<p>Thoracic aortic aneurysms and dissections (TAAD), a life-threatening complication of Marfan syndrome (MFS), lack curative therapies. Our previous studies revealed that versican accumulation drives MFS aortopathy through AKT-NO pathway overactivation, but the upstream mechanisms remained unclear. Here, we show that versican-driven fibronectin (FN) accumulation activates an α<sub>V</sub>β<sub>3</sub>-PI3K-PIP3-PDK1-ILK signaling cascade leading to AKT-NOS2 upregulation and aortic disease. FN accumulates in aortas of MFS patients and mice of both sexes and correlates with increased α<sub>V</sub>β<sub>3</sub> integrin and ILK expression. Disrupting FN assembly or inhibiting α<sub>V</sub>β<sub>3</sub>, PI3K, PIP3, PDK1 or ILK prevents FN-induced AKT activation and NOS2 upregulation, restores vascular contractility, and limits aortic dilation in MFS mice. Inhibition of ILK or PDK1, aortic silencing of <i>Ilk</i>, or smooth muscle-specific deletion of <i>Ilk</i> reverses or prevents aortic growth. Together, these findings define a mechanistically integrated FN-α<sub>V</sub>β<sub>3</sub>-PI3K-PIP3-PDK1-ILK-AKT-NOS2 signaling cascade in MFS and support its causative role in human TAAD, highlighting its components as potential targets for therapeutic intervention.</p>

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Fibronectin-induced overactivation of αVβ3-PI3K-PIP3-PDK1-ILK signaling drives aortic disease in Marfan syndrome

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月6日

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  • Iván Alarcón-Ruiz,
  • María Jesús Ruiz-Rodríguez,
  • Sara Martínez-Martínez,
  • Marta Toral,
  • Noelia Martín-Bermejo,
  • Sergio Mateos-García,
  • Teresa Gil-Ruiz,
  • Elías Herrero-Galán,
  • María José Méndez-Olivares,
  • Dolores López-Maderuelo,
  • Carolina Gutiérrez-Martínez,
  • Cristina Clemente,
  • Alejandro Clemente-Manteca,
  • Alberto H-Alcántara,
  • Andrea Guala,
  • Arturo Evangelista,
  • Gisela Teixido-Tura,
  • Diego Rodríguez-Puyol,
  • Juan Francisco Nistal,
  • Jorge Alegre-Cebollada,
  • Jesús Vázquez,
  • Juan Duarte,
  • Juan Miguel Redondo,
  • Miguel R. Campanero

摘要

Thoracic aortic aneurysms and dissections (TAAD), a life-threatening complication of Marfan syndrome (MFS), lack curative therapies. Our previous studies revealed that versican accumulation drives MFS aortopathy through AKT-NO pathway overactivation, but the upstream mechanisms remained unclear. Here, we show that versican-driven fibronectin (FN) accumulation activates an αVβ3-PI3K-PIP3-PDK1-ILK signaling cascade leading to AKT-NOS2 upregulation and aortic disease. FN accumulates in aortas of MFS patients and mice of both sexes and correlates with increased αVβ3 integrin and ILK expression. Disrupting FN assembly or inhibiting αVβ3, PI3K, PIP3, PDK1 or ILK prevents FN-induced AKT activation and NOS2 upregulation, restores vascular contractility, and limits aortic dilation in MFS mice. Inhibition of ILK or PDK1, aortic silencing of Ilk, or smooth muscle-specific deletion of Ilk reverses or prevents aortic growth. Together, these findings define a mechanistically integrated FN-αVβ3-PI3K-PIP3-PDK1-ILK-AKT-NOS2 signaling cascade in MFS and support its causative role in human TAAD, highlighting its components as potential targets for therapeutic intervention.