Tzima Eleni, Del Pozo Miguel Angel, Kiosses William B, Mohamed Samih A, Li Song, Chien Shu, Schwartz Martin Alexander
Department of Cell Biology, Division of Vascular Biology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA.
EMBO J. 2002 Dec 16;21(24):6791-800. doi: 10.1093/emboj/cdf688.
Hemodynamic shear stress is a fundamental determinant of vascular remodeling and atherogenesis. Changes in focal adhesions, cytoskeletal organization and gene expression are major responses of endothelial cells to shear stress. Here, we show that activation of the small GTPase Rac is essential for gene expression and for providing spatial information for shear stress-induced cell alignment. Fluorescence resonance energy transfer (FRET) localizes activated Rac1 in the direction of flow. This directional Rac1 activation is downstream of shear-induced new integrin binding to extracellular matrix. Additionally, Rac1 mediates flow-induced stimulation of nuclear factor kappaB (NF-kappaB) and the subsequent expression of intercellular cell adhesion molecule 1 (ICAM-1), an adhesion receptor involved in the recruitment of leukocytes to atherosclerotic plaque. These studies provide a unifying model linking three of the main responses to shear stress that mediate both normal adaptation to hemodynamic forces and inflammatory dysfunction of endothelial cells in atherosclerosis.
血流动力学切应力是血管重塑和动脉粥样硬化形成的一个基本决定因素。粘着斑、细胞骨架组织和基因表达的变化是内皮细胞对切应力的主要反应。在此，我们表明小GTP酶Rac的激活对于基因表达以及为切应力诱导的细胞排列提供空间信息至关重要。荧光共振能量转移（FRET）将活化的Rac1定位在血流方向上。这种定向的Rac1激活是切应力诱导新整合素与细胞外基质结合的下游事件。此外，Rac1介导血流诱导的核因子κB（NF-κB）激活以及随后细胞间黏附分子1（ICAM-1）的表达，ICAM-1是一种参与白细胞募集到动脉粥样硬化斑块的黏附受体。这些研究提供了一个统一模型，将对切应力的三种主要反应联系起来，这些反应既介导了对血流动力学力的正常适应，也介导了动脉粥样硬化中内皮细胞的炎症性功能障碍。
