Abnormal mechanosensing and cofilin activation promote the progression of ascending aortic aneurysms in mice

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Science Signaling  20 Oct 2015:
Vol. 8, Issue 399, pp. ra105
DOI: 10.1126/scisignal.aab3141

Aberrant mechanosensing and aneurysms

The smooth muscle cells in aortas are connected to the extracellular matrix. Mutations in components of the extracellular matrix, including one called fibulin-4, can weaken the aortic wall, leading to the enlargement of the aortic lumen, a condition known as an aneurysm. Yamashiro et al. found that mice with a smooth muscle cell–specific deficiency in fibulin-4 had disrupted connections between smooth muscle cells and the extracellular matrix, abnormal increases in mechanosensitive proteins, and enhanced activity of an actin cytoskeleton–remodeling enzyme called cofilin. These results suggest that mutations in extracellular matrix components that dispose patients to aneurysms may be due to an inability of the smooth muscle cells to respond appropriately to external mechanical forces. In addition, inhibiting the activity of cofilin or its activating phosphatase SSH1 could prevent the development of aneurysms.


Smooth muscle cells (SMCs) and the extracellular matrix (ECM) are intimately associated in the aortic wall. Fbln4SMKO mice with an SMC-specific deletion of the Fbln4 gene, which encodes the vascular ECM component fibulin-4, develop ascending aortic aneurysms that have increased abundance of angiotensin-converting enzyme (ACE); inhibiting angiotensin II signaling within the first month of life prevents aneurysm development. We used comparative proteomics analysis of Fbln4SMKO aortas from postnatal day (P) 1 to P30 mice to identify key molecules involved in aneurysm initiation and expansion. At P14, the actin depolymerizing factor cofilin was dephosphorylated and thus activated, and at P7, the abundance of slingshot-1 (SSH1) phosphatase, an activator of cofilin, was increased, leading to actin cytoskeletal remodeling. Also, by P7, biomechanical changes and underdeveloped elastic lamina–SMC connections were evident, and the abundance of early growth response 1 (Egr1), a mechanosensitive transcription factor that stimulates ACE expression, was increased, which was before the increases in ACE abundance and cofilin activation. Postnatal deletion of Fbln4 in SMCs at P7 prevented cofilin activation and aneurysm formation, suggesting that these processes required disruption of elastic lamina–SMC connections. Phosphoinositide 3-kinase (PI3K) is involved in the angiotensin II–mediated activation of SSH1, and administration of PI3K inhibitors from P7 to P30 decreased SSH1 abundance and prevented aneurysms. These results suggest that aneurysm formation arises from abnormal mechanosensing of SMCs resulting from the loss of elastic lamina–SMC connections and from increased SSH1 and cofilin activity, which may be potential therapeutic targets for treating ascending aortic aneurysms.

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