Research ArticleAortic aneurysm

Angiotensin-Converting Enzyme–Induced Activation of Local Angiotensin Signaling Is Required for Ascending Aortic Aneurysms in Fibulin-4–Deficient Mice

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Science Translational Medicine  01 May 2013:
Vol. 5, Issue 183, pp. 183ra58
DOI: 10.1126/scitranslmed.3005025

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ACEing Aortic Aneurysm Prevention

Aortic aneurysms, areas of abnormal dilation of the aorta, can be a fast and unexpected killer, striking unsuspecting patients without previous warning. These aneurysms can occur in patients with atherosclerosis, or even without any known risk factors, but they are particularly common in patients with Marfan syndrome and other types of connective tissue disease. Now, Huang et al. have created a mouse model of genetic predisposition to ascending aortic aneurysms and used it to test potential therapeutic interventions.

The mouse model presented by the authors lacks expression of fibulin-4 in vascular smooth muscle cells. Fibulin-4 normally contributes to the structure of elastic fibers and the contractile phenotype of smooth muscle cells in the vasculature. Mutations in the Fbln4 gene have been implicated in human connective tissue disease. The mice lacking vascular fibulin-4 protein predictably developed ascending aortic aneurysms early in life, and their blood vessel walls had a disorganized structure and disrupted elastic fibers. The authors showed that these mice also expressed abnormally high amounts of angiotensin-converting enzyme (ACE) in their ascending aortas, which caused abnormal extracellular signal–regulated kinase signaling through activation of angiotensin receptor 1. When the mutant animals were treated with captopril (an ACE inhibitor) or losartan (an angiotensin receptor blocker), thus interfering with the excess angiotensin signaling early in life, the aortic aneurysms did not develop.

This work by Huang and coauthors clarifies a mechanism of aortic aneurysm formation and provides some insight into a potential approach for intervention. Additional work will be needed to determine how much of this mechanism holds true in human patients (and in which subpopulations) and what intervention can help treat aneurysms after they have already formed.

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