Yamashiro Yoshito, Papke Christina L, Kim Jungsil, Ringuette Lea-Jeanne, Zhang Qing-Jun, Liu Zhi-Ping, Mirzaei Hamid, Wagenseil Jessica E, Davis Elaine C, Yanagisawa Hiromi
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Department of Mechanical Engineering and Materials Science, Washington University, St. Louis, MO 63130, USA.
Sci Signal. 2015 Oct 20;8(399):ra105. doi: 10.1126/scisignal.aab3141.
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.
平滑肌细胞（SMCs）与细胞外基质（ECM）在主动脉壁中紧密相连。Fbln4（SMKO）小鼠的平滑肌细胞特异性缺失编码血管ECM成分纤连蛋白-4的Fbln4基因，会发生升主动脉瘤，其血管紧张素转换酶（ACE）丰度增加；在出生后第一个月内抑制血管紧张素II信号传导可预防动脉瘤形成。我们对出生后第1天（P）至第30天的Fbln4（SMKO）主动脉进行了比较蛋白质组学分析，以确定参与动脉瘤起始和扩展的关键分子。在P14时，肌动蛋白解聚因子cofilin去磷酸化并因此被激活，在P7时，cofilin激活剂弹弓蛋白-1（SSH1）磷酸酶的丰度增加，导致肌动蛋白细胞骨架重塑。此外，到P7时，生物力学变化和弹性板-平滑肌细胞连接发育不全明显可见，刺激ACE表达的机械敏感转录因子早期生长反应1（Egr1）的丰度增加，这发生在ACE丰度增加和cofilin激活之前。在P7时平滑肌细胞中Fbln4的出生后缺失可防止cofilin激活和动脉瘤形成，表明这些过程需要破坏弹性板-平滑肌细胞连接。磷脂酰肌醇3-激酶（PI3K）参与血管紧张素II介导的SSH1激活，从P7到P30给予PI3K抑制剂可降低SSH1丰度并预防动脉瘤。这些结果表明，动脉瘤形成源于弹性板-平滑肌细胞连接丧失导致的平滑肌细胞异常机械传感以及SSH1和cofilin活性增加，这可能是治疗升主动脉瘤的潜在治疗靶点。
