Contribution of vascular calcineurin to arterial hypertension and abdominal aortic aneurysm formation
Title (trans.)Contribución de la calcineurina vascular a la hipertensión arterial y a la formación de aneurismas aórticos abdominales
EntityUAM. Departamento de Biología Molecular; Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)
SubjectsEnzimas; Hipertensión arterial; Patología clínica; Biología y Biomedicina / Biología
NoteTesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de Lectura: 29-06-2022
Esta tesis tiene embargado el acceso al texto completo hasta el 21-11-2026
Esta obra está bajo una licencia de Creative Commons Reconocimiento-NoComercial-SinObraDerivada 4.0 Internacional.
Understanding the pathophysiological bases of vascular remodeling is essential to improve current therapies in cardiovascular disease. Pathological remodeling of the vascular wall and arterial hypertension are common features of arterial pathophysiology. Angiotensin II (Ang-II), the major effector of the renin-angiotensin system, plays an essential role in vascular damage. Previous studies identified the Calcineurin (Cn)/NFAT pathway as a mediator of Ang-II-induced vascular remodeling. Cn is a phosphatase that binds to and dephosphorylates NFAT, among other substrates. Although Cn has been involved in Ang-II-induced abdominal aortic aneurysm (AAA) and neointimal thickening, the relative contribution of Cn from different vascular cell compartments to the development of these pathologies remains unknown. In this Thesis, we have generated conditional and inducible Cn deficient mice to study the relative contribution of smooth muscle (SM-KO) and endothelial (EC-KO) Cn in the development of vascular pathologies. We have found that Cn plays an essential role in AAA and in Ang-II-induced arterial hypertension. Remarkably, only SM-KO mice were resistant to these two pathologies, and no protection was observed in the EC-KO. Strikingly, the treatment with Cn phosphatase activity inhibitors, Cyclosporine A (CsA) or the LxVP peptide, did not protect from Ang- II-induced hypertension, suggesting a phosphatase activity-independent role for smooth muscle Cn in this protection. In contractility studies, aortic and mesenteric arteries from SM-KO mice and Cn-deficient vascular smooth muscle cells (VSMCs) showed decreased contractile capacity in response to various stimuli. Ang-II-induced hypertension was detected as early as 2 hours, and at this time we already observed protection in SM-KO mice. The transcriptomic, proteomic, and phospho-proteomic (p-proteomic) profiles of aortas from Control and SM-KO mice treated with Ang-II were largely dependent on smooth muscle Cn. Indeed, nearly 90% of differentially expressed genes (DEGs) required Cn expression, whereas only nearly 33% of DEGs required Cn phosphatase activity. Among the Ang-II-regulated genes that required Cn expression but not its activity we found mostly genes related to contractility and inflammatory processes. In summary, the results of the Thesis show an essential role of smooth muscle Cn in the initiation and maintenance of Ang-II-mediated hypertension and in the remodeling that occurs in AAA. These results have also allowed the identification of mediators of potential interest as targets for therapeutic intervention in these pathologies
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