title: Regulator of calcineurin 1 mediates pathological vascular wall remodeling.
abstract: Artery 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.
authors.affiliation: Department of Vascular Biology and Inflammation, Centro Nacional de Investigaciones Cardiovasculares (CNIC), E-28029 Madrid, Spain.
authors.forename: Vanesa
authors.initials: V
authors.lastname: Esteban
authors.forename: Nerea
authors.initials: N
authors.lastname: Méndez-Barbero
authors.forename: Luis Jesús
authors.initials: LJ
authors.lastname: Jiménez-Borreguero
authors.forename: Mercè
authors.initials: M
authors.lastname: Roqué
authors.forename: Laura
authors.initials: L
authors.lastname: Novensá
authors.forename: Ana Belén
authors.initials: AB
authors.lastname: García-Redondo
authors.forename: Mercedes
authors.initials: M
authors.lastname: Salaices
authors.forename: Luis
authors.initials: L
authors.lastname: Vila
authors.forename: María L
authors.initials: ML
authors.lastname: Arbonés
authors.forename: Miguel R
authors.initials: MR
authors.lastname: Campanero
authors.forename: Juan Miguel
authors.initials: JM
authors.lastname: Redondo
mesh_terms: D000783:Aneurysm / Q000473:pathology* / Q000503:physiopathology; D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000473:pathology; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism*; D002135:Calcium-Binding Proteins; D002465:Cell Movement; D023903:Coronary Restenosis / Q000473:pathology* / Q000503:physiopathology; D016572:Cyclosporine / Q000378:metabolism; D005786:Gene Expression Regulation; D007166:Immunosuppressive Agents / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000473:pathology* / Q000502:physiology*; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology
chemical_list: D002135:Calcium-Binding Proteins; C511512:DSCR1 protein, mouse; D007166:Immunosuppressive Agents; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D050778:NFATC Transcription Factors; D000804:Angiotensin II; D016572:Cyclosporine; D019703:Calcineurin