Age-related intimal stiffening enhances endothelial permeability and leukocyte transmigration.
Age-related intimal stiffening enhances endothelial permeability and leukocyte transmigration.
复制标题
DOI：
10.1126/scitranslmed.3002761
复制
发表时间：
2011-12-07
影响因子：
17.1
通讯作者：
Reinhart-King CA
中科院分区：
文献类型：
--
作者：
Huynh J;Nishimura N;Rana K;Peloquin JM;Califano JP;Montague CR;King MR;Schaffer CB;Reinhart-King CA
年龄是动脉粥样硬化最重要的危险因素;然而，年龄和动脉粥样硬化之间的联系知之甚少。在衰老和动脉粥样硬化进展过程中，血管壁由于细胞外基质的改变而变硬。使用血管壁僵硬和老化的体外和离体模型，我们发现内膜内细胞外基质的硬化促进了内皮细胞的渗透性动脉粥样硬化形成的标志。当在与年轻和老化内膜的弹性相匹配的水凝胶上培养时，内皮单层表现出增加的渗透性和破坏的细胞-细胞连接。在平行实验中，我们发现年轻（10周）和老年（21至25个月）健康小鼠的离体动脉中细胞-细胞连接宽度随年龄相应增加。为了研究基质硬化改变单层完整性的机制，我们发现细胞收缩性随着基质硬度的增加而增加，机械上破坏了细胞-细胞连接。内皮通透性的增加导致白细胞外渗增加，这是动脉粥样硬化斑块形成的关键步骤。使用Y-27632（Rho相关激酶的抑制剂）或siRNA对Rho依赖性细胞收缩性的轻度抑制在体外和体内恢复了单层完整性。我们的研究结果表明，细胞外基质硬化，这发生在老化过程中，可导致内皮细胞单层破坏和动脉粥样硬化的发病机制。由于先前设计用于降低血管硬度的治疗方法已取得有限的成功，因此我们的研究结果可能是设计治疗方法的基础，这些治疗方法靶向Rho依赖性细胞收缩反应对基质硬化，而不是硬化本身，以更有效地预防动脉粥样硬化进展。
Age is the most significant risk factor for atherosclerosis; however, the link between age and atherosclerosis is poorly understood. During both aging and atherosclerosis progression, the blood vessel wall stiffens owing to alterations in the extracellular matrix. Using in vitro and ex vivo models of vessel-wall stiffness and aging, we show that stiffening of extracellular matrix within the intima promotes endothelial cell permeability—a hallmark of atherogenesis. When cultured on hydrogels fabricated to match the elasticity of young and aging intima, endothelial monolayers exhibit increased permeability and disrupted cell-cell junctions on stiffer matrices. In parallel experiments, we showed a corresponding increase in cell-cell junction width with age in ex vivo aortas from young (10 weeks) and old (21 to 25 months) healthy mice. To investigate the mechanism by which matrix stiffening alters monolayer integrity, we found that cell contractility increases with increased matrix stiffness, mechanically destabilizing cell-cell junctions. This increase in endothelial permeability results in increased leukocyte extravasation, which is a critical step in atherosclerotic plaque formation. Mild inhibition of Rho-dependent cell contractility using Y-27632, an inhibitor of Rho-associated kinase, or siRNA restored monolayer integrity in vitro and in vivo. Our results suggest that extracellular matrix stiffening alone, which occurs during aging, can lead to endothelial monolayer disruption and atherosclerosis pathogenesis. Because previous therapeutics designed to decrease vascular stiffness have been met with limited success, our findings could be the basis for the design of therapeutics that target the Rho-dependent cellular contractile response to matrix stiffening, rather than stiffness itself, to more effectively prevent atherosclerosis progression.
登录
查看更多内容
影响因子：
4
作者：
Dejana, Elisabetta;Orsenigo, Fabrizio;Lampugnani, Maria Grazia
通讯作者：
Lampugnani, Maria Grazia
影响因子：
7.4
作者：
Dong, Ming;Yan, Bryan P.;Liao, James K.;Lam, Yat-Yin;Yip, Gabriel W. K.;Yu, Cheuk-Man
通讯作者：
Yu, Cheuk-Man
影响因子：
8.3
作者：
Blacher, J;Asmar, R;Safar, ME
通讯作者：
Safar, ME
影响因子：
3.3
作者：
COOPER, JA;DELVECCHIO, PJ;MALIK, AB
通讯作者：
MALIK, AB
影响因子：
3.4
作者：
Dembo, M;Wang, YL
通讯作者：
Wang, YL