Send to

Choose Destination
Sci Transl Med. 2013 May 1;5(183):183ra58, 1-11. doi: 10.1126/scitranslmed.3005025.

Angiotensin-converting enzyme-induced activation of local angiotensin signaling is required for ascending aortic aneurysms in fibulin-4-deficient mice.

Author information

Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148.
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148.
Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-9050.
Department of Biochemistry, School of Medicine, Vanderbilt University, Nashville, TN 37235.
Department of Biomedical Engineering, St. Louis University, St. Louis, MO 63103-2010.
Contributed equally


Aortic aneurysms are life-threatening and often associated with defects in connective tissues and mutations in smooth muscle cell (SMC) contractile proteins. Despite recent advances in understanding altered signaling in aneurysms of Marfan syndrome, the underlying mechanisms and options for pharmacological treatment for other forms of aneurysms are still under investigation. We previously showed in mice that deficiency in the fibulin-4 gene in vascular SMCs (Fbln4(SMKO)) leads to loss of the SMC contractile phenotype, hyperproliferation, and ascending aortic aneurysms. We report that abnormal up-regulation of angiotensin-converting enzyme (ACE) in SMCs and subsequent activation of angiotensin II (AngII) signaling are involved in the onset of aortic aneurysms in Fbln4(SMKO) mice. In this model, aneurysm formation was completely prevented by inhibition of the AngII pathway with losartan or captopril within a narrow therapeutic window during the first month of life, even though the altered mechanical properties of blood vessel walls were not reversed by the pharmacological treatment. The therapeutic effects of losartan in Fbln4(SMKO) mice do not require the AngII receptor type 2 (Agtr2) but likely require both type 1a (Agtr1a) and 1b (Agtr1b) receptors. The results indicate that fibulin-4 is a vascular matrix component required for regulation of local angiotensin signaling and development and maintenance of the SMC phenotype.

[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Grant support

Publication types

MeSH terms


Grant support

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center