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Title

Regulator of calcineurin 1 mediates pathological vascular wall remodeling

AuthorsEsteban, Vanesa; Arbones, Maria L. ; Campanero, Miguel R. ; Redondo, Juan Miguel
Issue Date2011
PublisherRockefeller University Press
CitationJournal of Experimental Medicine 208(10): 2125-2139 (2011)
AbstractArtery wall remodeling, a major feature of diseases such as hypertension, restenosis, atherosclerosis, and aneurysm, involves changes in the tunica media mass that reduce or increase the vessel lumen. The identification of molecules involved in vessel remodeling could aid the development of improved treatments for these pathologies. Angiotensin II (AngII) is a key effector of aortic wall remodeling that contributes to aneurysm formation and restenosis through incompletely defined signaling pathways. We show that AngII induces vascular smooth muscle cell (VSMC) migration and vessel remodeling in mouse models of restenosis and aneurysm. These effects were prevented by pharmacological inhibition of calcineurin (CN) or lentiviral delivery of CN-inhibitory peptides. Whole-genome analysis revealed >1,500 AngII-regulated genes in VSMCs, with just 11 of them requiring CN activation. Of these, the most sensitive to CN activation was regulator of CN 1 (Rcan1). Rcan1 was strongly activated by AngII in vitro and in vivo and was required for AngII-induced VSMC migration. Remarkably, Rcan1(-/-) mice were resistant to AngII-induced aneurysm and restenosis. Our results indicate that aneurysm formation and restenosis share mechanistic elements and identify Rcan1 as a potential therapeutic target for prevention of aneurysm and restenosis progression
DescriptionThis article is distributed under a Creative Commons License Attribution–Noncommercial–Share Alike 3.0 Unported license.-- et al.
Publisher version (URL)http://dx.doi.org/10.1084/jem.20110503
URIhttp://hdl.handle.net/10261/77828
DOI10.1084/jem.20110503
Identifiersdoi: 10.1084/jem.20110503
issn: 0022-1007
e-issn: 1540-9538
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