Conditional deletion of Rcan1 predisposes to hypertension-mediated intramural hematoma and subsequent aneurysm and aortic rupture

Silvia Villahoz, Paula Sofía Yunes-Leites, Nerea Méndez-Barbero, Katia Urso, Elena Bonzon-Kulichenko, Sagrario Ortega, J. Francisco Nistal, Jesus Vazquez, Stefan Offermanns, Juan Miguel Redondo () and Miguel R. Campanero ()
Additional contact information
Silvia Villahoz: Gene regulation in cardiovascular remodeling and inflammation group, Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Paula Sofía Yunes-Leites: Gene regulation in cardiovascular remodeling and inflammation group, Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Nerea Méndez-Barbero: Gene regulation in cardiovascular remodeling and inflammation group, Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Katia Urso: Gene regulation in cardiovascular remodeling and inflammation group, Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Elena Bonzon-Kulichenko: Centro de Investigaciones Biomédicas en RED en Enfermedades Cardiovasculares (CIBERCV)
Sagrario Ortega: Centro Nacional de Investigaciones Oncológicas (CNIO)
J. Francisco Nistal: Centro de Investigaciones Biomédicas en RED en Enfermedades Cardiovasculares (CIBERCV)
Jesus Vazquez: Centro de Investigaciones Biomédicas en RED en Enfermedades Cardiovasculares (CIBERCV)
Stefan Offermanns: Max Planck Institute for Heart and Lung Research
Juan Miguel Redondo: Gene regulation in cardiovascular remodeling and inflammation group, Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Miguel R. Campanero: Centro de Investigaciones Biomédicas en RED en Enfermedades Cardiovasculares (CIBERCV)

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: Abstract Aortic intramural hematoma (IMH) can evolve toward reabsorption, dissection or aneurysm. Hypertension is the most common predisposing factor in IMH and aneurysm patients, and the hypertensive mediator angiotensin-II induces both in mice. We have previously shown that constitutive deletion of Rcan1 isoforms prevents Angiotensin II-induced aneurysm in mice. Here we generate mice conditionally lacking each isoform or all isoforms in vascular smooth muscle cells, endothelial cells, or ubiquitously, to determine the contribution to aneurysm development of Rcan1 isoforms in vascular cells. Surprisingly, conditional Rcan1 deletion in either vascular cell-type induces a hypercontractile phenotype and aortic medial layer disorganization, predisposing to hypertension-mediated aortic rupture, IMH, and aneurysm. These processes are blocked by ROCK inhibition. We find that Rcan1 associates with GSK-3β, whose inhibition decreases myosin activation. Our results identify potential therapeutic targets for intervention in IMH and aneurysm and call for caution when interpreting phenotypes of constitutively and inducibly deficient mice.

Date: 2018
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DOI: 10.1038/s41467-018-07071-7

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