In collaboration with Miguel Campanero’s group, we identified key HTAD mediators, including Adamts1, Nos2, C/EBPβ, Plk1, and Rcan1. Adamts1 deficiency induces aortic disease via NOS2-mediated NO overproduction, and NOS2 inhibitors prevent and reverse pathology in MFS and Adamts1 mouse models. We also found that the NO-sGC-PKG pathway is overactivated in MFS due to extracellular matrix protein accumulation, including Versican (Vcan) and Fibronectin (FN), which activate the AKT-NOS2 pathway. Genetic Vcan deficiency, lentiviral silencing, or AKT inhibition reversed aortic dilation, highlighting new therapeutic targets. Additionally, FN accumulation promotes MFS aortopathy via integrin signaling, initiating a cascade we have characterized in detail. Mapping these pathways represents a major breakthrough, establishing the most comprehensive signaling network in MFS aortopathy to date and linking extracellular matrix alterations with AKT-NO and integrin-mediated signaling. Our data also suggest that the AKT-NOS2 pathway, previously linked to MFS, also plays a role in LDS, warranting further investigation.

Furthermore, in collaboration with Jesús Vázquez’s group at CNIC, we conducted proteomic analyses that identified sex-dependent and independent molecular signatures in MFS and LDS, revealing shared patterns absent in controls and distinct clusters differentiating the syndromes. This work has enabled us to identify common mediators, syndrome-specific proteins, and sex-associated markers, all of which require further characterization. Additionally, we identified plasma proteins in MFS patients with high diagnostic accuracy and correlation with clinical severity, supporting their validation as diagnostic and prognostic biomarkers.

Overall, our research aims to provide new insights into HTAD pathophysiology and open avenues for therapeutic target discovery and biomarker development in aortic diseases.