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

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.CNIC is supported by the Spanish Ministerio de Ciencia, Investigación y Universidades (MINECO) and the Pro-CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). Support was also provided by grants from MINECO (grants SAF2013- 45258P and SAF2017-88881R (M.R.C.), SAF2015-636333R (J.M.R.), PI15/01224 (J.F.N.), and BIO2015-67580-P (J.V.)), Comunidad de Madrid (grant AORTASANA-CM; B2017/ BMD-3676 (M.R.C. and J.M.R.)), CSIC (M.R.C.), Fundacion La Marato TV3 (grant 20151330 (J.M.R.)), The Marfan Foundation Faculty grant 2017 (J.M.R.), and the CIBERCV of Ministerio de Sanidad (grants CB16/11/00264 (J.M.R.) and CB16/11/00277 (J.V.)). S.V. and P.S.Y.-L. hold FPI fellowships SVP-2013-067777 and BES-2016-076637, respectively. The cost of this publication was paid in part with FEDER funds.Peer reviewe