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oai:repisalud.isciii.es:20.500.12105/67392024-11-29T21:54:08Zcom_20.500.12105_19604com_20.500.12105_2051com_20.500.12105_2173col_20.500.12105_19605col_20.500.12105_19597

00925njm 22002777a 4500 dc Villahoz, Silvia author Yunes-Leites, Paula Sofia author Mendez-Barbero, Nerea author Urso, Katia author Bonzon-Kulichenko, Elena author Ortega Jimenez, Sagrario author Nistal, J Francisco author Vazquez, Jesus author Offermanns, Stefan author Redondo, Juan Miguel author Campanero, Miguel R author 2018-11-15 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. Nat Commun. 2018; 9(1): 4795. 10.1038/s41467-018-07071-7 2041-1723 2041-1723 Nature communications 30442942 http://hdl.handle.net/20.500.12105/6739 SYNDROME CRITICAL REGION CALCINEURIN INHIBITOR DSCR1 VASCULAR SMOOTH-MUSCLE PEPTIDE IDENTIFICATION STRIATED-MUSCLES OXIDATIVE STRESS CELL-MIGRATION TUMOR-GROWTH 1 GENE MICE Conditional deletion of Rcan1 predisposes to hypertension-mediated intramural hematoma and subsequent aneurysm and aortic rupture