title: Impaired vascular contractility and aortic wall degeneration in fibulin-4 deficient mice: effect of angiotensin II type 1 (AT1) receptor blockade.
abstract: Medial degeneration is a key feature of aneurysm disease and aortic dissection. In a murine aneurysm model we investigated the structural and functional characteristics of aortic wall degeneration in adult fibulin-4 deficient mice and the potential therapeutic role of the angiotensin (Ang) II type 1 (AT(1)) receptor antagonist losartan in preventing aortic media degeneration. Adult mice with 2-fold (heterozygous Fibulin-4(+/R)) and 4-fold (homozygous Fibulin-4(R/R)) reduced expression of fibulin-4 displayed the histological features of cystic media degeneration as found in patients with aneurysm or dissection, including elastin fiber fragmentation, loss of smooth muscle cells, and deposition of ground substance in the extracellular matrix of the aortic media. The aortic contractile capacity, determined by isometric force measurements, was diminished, and was associated with dysregulation of contractile genes as shown by aortic transcriptome analysis. These structural and functional alterations were accompanied by upregulation of TGF-β signaling in aortas from fibulin-4 deficient mice, as identified by genome-scaled network analysis as well as by immunohistochemical staining for phosphorylated Smad2, an intracellular mediator of TGF-β. Tissue levels of Ang II, a regulator of TGF-β signaling, were increased. Prenatal treatment with the AT(1) receptor antagonist losartan, which blunts TGF-β signaling, prevented elastic fiber fragmentation in the aortic media of newborn Fibulin-4(R/R) mice. Postnatal losartan treatment reduced haemodynamic stress and improved lifespan of homozygous knockdown fibulin-4 animals, but did not affect aortic vessel wall structure. In conclusion, the AT(1) receptor blocker losartan can prevent aortic media degeneration in a non-Marfan syndrome aneurysm mouse model. In established aortic aneurysms, losartan does not affect aortic architecture, but does improve survival. These findings may extend the potential therapeutic application of inhibitors of the renin-angiotensin system to the preventive treatment of aneurysm disease.
authors.affiliation: Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Els
authors.initials: E
authors.lastname: Moltzer
authors.forename: Luuk
authors.initials: L
authors.lastname: te Riet
authors.forename: Sigrid M A
authors.initials: SM
authors.lastname: Swagemakers
authors.forename: Paula M
authors.initials: PM
authors.lastname: van Heijningen
authors.forename: Marcel
authors.initials: M
authors.lastname: Vermeij
authors.forename: Richard
authors.initials: R
authors.lastname: van Veghel
authors.forename: Angelique M
authors.initials: AM
authors.lastname: Bouhuizen
authors.forename: Joep H M
authors.initials: JH
authors.lastname: van Esch
authors.forename: Stephanie
authors.initials: S
authors.lastname: Lankhorst
authors.forename: Natasja W M
authors.initials: NW
authors.lastname: Ramnath
authors.forename: Monique C
authors.initials: MC
authors.lastname: de Waard
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: Duncker
authors.forename: Peter J
authors.initials: PJ
authors.lastname: van der Spek
authors.forename: Ellen V
authors.initials: EV
authors.lastname: Rouwet
authors.forename: A H Jan
authors.initials: AH
authors.lastname: Danser
authors.forename: Jeroen
authors.initials: J
authors.lastname: Essers
mesh_terms: D000804:Angiotensin II / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001013:Aorta, Thoracic / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D001014:Aortic Aneurysm / Q000235:genetics / Q000503:physiopathology* / Q000517:prevention & control; D016326:Extracellular Matrix Proteins / Q000172:deficiency* / Q000235:genetics; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D019808:Losartan / Q000494:pharmacology; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D010656:Phenylephrine / Q000494:pharmacology; D011247:Pregnancy; D044140:Receptor, Angiotensin, Type 1 / Q000502:physiology; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; C403672:EFEMP2 protein, human; D016326:Extracellular Matrix Proteins; D044140:Receptor, Angiotensin, Type 1; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D016212:Transforming Growth Factor beta; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D010656:Phenylephrine; D019808:Losartan