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

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.