Abnormal mechanosensing and cofilin activation promote the progression of ascending aortic aneurysms in mice.
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.
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Yoshito
Y
Yamashiro
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Christina L
CL
Papke
Department of Mechanical Engineering and Materials Science, Washington University, St. Louis, MO 63130, USA.
Jungsil
J
Kim
Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec H3A 0C7, Canada.
Lea-Jeanne
LJ
Ringuette
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Qing-Jun
QJ
Zhang
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Zhi-Ping
ZP
Liu
Department of Biochemistry and Proteomics Core Unit, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Hamid
H
Mirzaei
Department of Mechanical Engineering and Materials Science, Washington University, St. Louis, MO 63130, USA.
Jessica E
JE
Wagenseil
Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec H3A 0C7, Canada.
Elaine C
EC
Davis
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Life Science Center of Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba 305-8577, Japan. hkyanagisawa@tara.tsukuba.ac.jp.
Hiromi
H
Yanagisawa
D051339:Actin Depolymerizing Factors / Q000502:physiology*; D000818:Animals; D001014:Aortic Aneurysm / Q000503:physiopathology*; D018450:Disease Progression; D051379:Mice
D051339:Actin Depolymerizing Factors