Fibronectin-induced overactivation of α<sub>V</sub>β<sub>3</sub>-PI3K-PIP3-PDK1-ILK signaling drives aortic disease in Marfan syndrome.
basic_science · Level V
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- Record sourced from PubMed, PMID 42409814.
- Also identified by DOI 10.1038/s41467-026-74707-4.
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Abstract
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 Ilk, or smooth muscle-specific deletion of Ilk 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.