Marfan mouse and human aortic tissue

ABSTRACT: Thoracic aortic aneurysms and dissections (TAAD), as occur in Marfan syndrome (MFS), currently lack a cure. Our previous studies revealed that overactivation of the AKT-NO signaling pathway mediates aortic disease in MFS. However, the mechanisms upstream of AKT activation remained poorly understood. Here we identify the Fibronectin-αVβ3-PI3K-PIP3-PDK1-ILK cascade as a critical mediator of AKT-NOS2 upregulation and aortic disease in MFS. We show that fibronectin (FN) accumulates in the walls of human and mouse MFS aortas. Disrupting FN multimerization inhibits AKT activation and NOS2 induction in vascular smooth muscle cells (VSMCs), prevents aortic contractility dysregulation, and reverses aortic dilation in MFS mice. Mechanistically, both human and mouse MFS aortas exhibit αVβ3 and ILK upregulation. Pharmacological inhibition of αVβ3, PI3K, PDK1, and ILK, or their recruitment to the plasma membrane by PIP3, prevents FN-induced AKT activation and NOS2 upregulation in VMSCs and aortic contractility dysregulation. Furthermore, ILK inhibition or aortic silencing reverses aortic disease, while its deletion in smooth muscle cells prevents aortic growth in MFS mice. These findings establish the most thoroughly characterized pathway implicated in MFS to date and suggest a causative role for the FN-αVβ3-PI3K-PIP3-PDK1-ILK-AKT-NOS2 cascade in human TAAD, highlighting its components as potential targets for therapeutic intervention.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human) Mus Musculus (mouse)

TISSUE(S): Aorta

DISEASE(S): Marfan Syndrome

SUBMITTER: Emilio Camafeita  

LAB HEAD: Jesús Vázquez

PROVIDER: PXD077940 | Pride | 2026-06-02

REPOSITORIES: Pride