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

Yoshito Yamashiro, Christina L. Papke, Jungsil Kim, Lea Jeanne Ringuette, Qing Jun Zhang, Zhi Ping Liu, Hamid Mirzaei, Jessica E. Wagenseil, Elaine C. Davis, Hiromi Yanagisawa

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22 Scopus citations

Abstract

Smooth muscle cells (SMCs) and the extracellular matrix (ECM) are intimately associated in the aortic wall. Fbln4(SMKO) 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 Fbln4(SMKO) 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.

Original languageEnglish (US)
Pages (from-to)ra105
JournalScience Signaling
Volume8
Issue number399
DOIs
Publication statusPublished - Oct 20 2015

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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