2026-07-26T08:12:58Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/275962026-07-17T00:15:49Zcom_20.500.12105_19586com_20.500.12105_2202col_20.500.12105_19587

00925njm 22002777a 4500 dc Alarcón-Ruiz, Iván author Ruiz-Rodríguez, María Jesús author Martínez-Martínez, Sara author Toral, Marta author Martín-Bermejo, Noelia author Mateos-García, Sergio author Gil-Ruiz, Teresa author Herrero-Galán, Elías author Méndez-Olivares, María José author López-Maderuelo, Dolores author Gutiérrez-Martínez, Carolina author Clemente, Cristina author Clemente-Manteca, Alejandro author H-Alcántara, Alberto author Guala, Andrea author Evangelista, Arturo author Teixido-Tura, Gisela author Rodríguez-Puyol, Diego author Nistal, Juan Francisco author Alegre-Cebollada, Jorge author Vázquez, Jesús author Duarte, Juan author Redondo, Juan Miguel author Campanero, Miguel R author 2026-07-06 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 αβ-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 αβ integrin and ILK expression. Disrupting FN assembly or inhibiting αβ, 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-αβ-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. Nat Commun. 2026 Jul 6;17(1):5631. NATURE COMMUNICATIONS 42409814 https://hdl.handle.net/20.500.12105/27596 Fibronectin-induced overactivation of αβ-PI3K-PIP3-PDK1-ILK signaling drives aortic disease in Marfan syndrome.