Document Detail

Impaired vascular contractility and aortic wall degeneration in fibulin-4 deficient mice: effect of angiotensin II type 1 (AT1) receptor blockade.
MedLine Citation:
PMID:  21858106     Owner:  NLM     Status:  MEDLINE    
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.
Els Moltzer; Luuk te Riet; Sigrid M A Swagemakers; Paula M van Heijningen; Marcel Vermeij; Richard van Veghel; Angelique M Bouhuizen; Joep H M van Esch; Stephanie Lankhorst; Natasja W M Ramnath; Monique C de Waard; Dirk J Duncker; Peter J van der Spek; Ellen V Rouwet; A H Jan Danser; Jeroen Essers
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, Non-U.S. Gov't     Date:  2011-08-09
Journal Detail:
Title:  PloS one     Volume:  6     ISSN:  1932-6203     ISO Abbreviation:  PLoS ONE     Publication Date:  2011  
Date Detail:
Created Date:  2011-08-22     Completed Date:  2012-02-15     Revised Date:  2013-06-27    
Medline Journal Info:
Nlm Unique ID:  101285081     Medline TA:  PLoS One     Country:  United States    
Other Details:
Languages:  eng     Pagination:  e23411     Citation Subset:  IM    
Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
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MeSH Terms
Angiotensin II / genetics,  metabolism,  pharmacology
Angiotensin II Type 1 Receptor Blockers / pharmacology
Animals, Newborn
Aorta, Thoracic / metabolism,  pathology,  physiopathology*
Aortic Aneurysm / genetics,  physiopathology*,  prevention & control
Extracellular Matrix Proteins / deficiency*,  genetics
Losartan / pharmacology
Mice, 129 Strain
Mice, Inbred C57BL
Mice, Knockout
Oligonucleotide Array Sequence Analysis
Phenylephrine / pharmacology
Receptor, Angiotensin, Type 1 / physiology
Smad2 Protein / genetics,  metabolism
Transforming Growth Factor beta / genetics,  metabolism
Vasoconstriction / drug effects,  genetics,  physiology*
Vasoconstrictor Agents / pharmacology
Reg. No./Substance:
0/Angiotensin II Type 1 Receptor Blockers; 0/Extracellular Matrix Proteins; 0/Receptor, Angiotensin, Type 1; 0/SMAD2 protein, human; 0/Smad2 Protein; 0/Transforming Growth Factor beta; 0/Vasoconstrictor Agents; 0/fibulin-4; 11128-99-7/Angiotensin II; 114798-26-4/Losartan; 59-42-7/Phenylephrine

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