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 abdominalesAuthor
Yunes Leites, SofíaEntity
UAM. Departamento de Biología Molecular; Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)Date
2022-06-29Subjects
Enzimas; Hipertensión arterial; Patología clínica; Biología y Biomedicina / BiologíaNote
Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de Lectura: 29-06-2022Esta 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.
Abstract
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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