Role of Adamts1 substrates and nitric oxide synthases in Marfan syndrome aortopathy

• Autores: María Jesús Ruiz Rodríguez
• Directores de la Tesis: Juan Miguel Redondo Moya (dir. tes.), Miguel Campanero Garcia (codir. tes.)
• Lectura: En la Universidad Autónoma de Madrid ( España ) en 2022
• Idioma: inglés
• Número de páginas: 189
• Tribunal Calificador de la Tesis: Carmelo Bernabeu Quirante (presid.), Jorge Alegre Cebollada (secret.), Ángel Luis Armesilla Arpa (voc.)
• Programa de doctorado: Programa de Doctorado en Biociencias Moleculares por la Universidad Autónoma de Madrid
• Materias:
  • Ciencias médicas
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• Resumen

  • Thoracic aortic aneurysm and dissection (TAAD) can involve life-threatening bleeding and is associated with Marfan syndrome (MFS), a disease caused by mutations in FBN1, a gene encoding fibrillin-1. Pathological vascular wall remodeling, a major feature of aortic aneurysms and dissections, implies uncontrolled extracellular matrix (ECM) remodeling and dysregulated vascular smooth muscle cell (VSMC) proliferation, migration and differentiation. Previous studies have identified the ECM metalloproteinase Adamts1 as a major mediator of vascular homeostasis, whose genetic deficiency in mice induces an aortic phenotype similar to MFS. Of note, reduced ADAMTS1, enhanced levels of NOS2 and an overactivated nitric oxide (NO) signaling pathway have been found in mice and patients with MFS. However, the molecular mechanisms underlying NOS2 overexpression in MFS remain unknown. In this thesis, we study the functional role of Adamts1 substrates as well as the contribution of Nos1 and Nos3 to aortic pathology in the Fbn1C1039G/+ MFS mouse model. We show that Versican, but not Aggrecan, accumulates in the aortic wall of MFS mice. Moreover, Versican knockdown, but not Aggrecan silencing, completely reversed aortic dilatation and medial degeneration by decreasing Nos2 expression. Accordingly, Versican haploinsufficiency conferred partial protection against aortic enlargement in this mouse model of MFS. We have also analysed the signaling pathways that could be activated by Versican accumulation. As Adamts1 knockdown triggers Akt activation, we addressed the role of this pathway in MFS aortopathy and found that pharmacological inhibition of the Akt signaling pathway in MFS mice rapidly regressed aortic dilatation and Nos2 expression.

    Likewise, inhibition of Ilk, an upstream kinase of Akt highly related to integrins, quickly reversed MFS aortic dilatation and restored Nos2 expression to basal levels through inhibition of the mTOR/Akt signaling pathway. Since pharmacological inhibition of Nos2 with 1400W or all Nos with L-NAME completely reversed aortopathy in Adamts1+/- and MFS mice, we have also analysed the contribution of the three NOS proteins to MFS aortopathy. We found that, contrary to Nos1-deficient MFS mice, both Nos2- and Nos3-deficient MFS mice were protected from aneurysm formation. Although Nos2 deficiency protected MFS mice from aortopathy, biaxial mechanical studies revealed that Nos2 deficiency did not improve biomechanical function in MFS aortas ex vivo. Taken together, our findings provide new mediators and promising targets for MFS aortic pathology, including Versican, mTOR/Akt, Ilk, Nos2 and Nos3.