Choosing sides in polarized endothelial adaptation to shear stress.
Choosing sides in polarized endothelial adaptation to shear stress.
复制标题
选择极化内皮适应剪切应力的一侧。
DOI：
10.1161/circresaha.108.180836
复制
发表时间：
2008
影响因子：
20.1
通讯作者：
Helmke,BrianP
中科院分区：
文献类型：
--
作者：
Helmke,BrianP
内皮是指导血管壁生理学和病理学的生物物理和化学线索的主要整合者。正常情况下，动脉内皮细胞呈纵向拉长，并位于 IV 型胶原蛋白和层粘连蛋白的基底膜上。在动脉粥样硬化中，病变主要形成于动脉分叉附近和沿着主动脉的内曲率，其中存在复杂的血流动力学力的时空分布，并且内皮细胞表现出非极化结构并上调富含纤连蛋白和纤维蛋白原的临时基质的表达。内皮表型和基质表达的区域异质性表明，病变进展需要将与血流动力学壁剪切应力和动脉壁拉伸相关的机械信号转导为炎症的生化信号。整合素已被提议作为能够区分物理信号和基质组成的候选机械传感器，但赋予剪切应力响应方向性的整合素介导机制仍然难以捉摸。在本期《循环研究》中，Goldfinger 等人报道，剪切应力激活蛋白激酶 A (PKA)，在内皮细胞下游边缘局部磷酸化 α4 整合素，磷酸化的 α4 释放对 GTPase Rac1 的抑制，从而指导细胞骨架的极化重组。所提出的机制很重要，不仅因为它提高了对机械转导机制中细胞内空间组织的理解，而且因为它提出了在旁路移植或血管支架手术后设计健康内皮的新途径。
The endothelium is a primary integrator of biophysical and chemical cues that guide vascular wall physiology and pathology. Normally, arterial endothelial cells appear elongated longitudinally and rest on a basement membrane of collagen type IV and laminin. In atherosclerosis, lesions form primarily near arterial bifurcations and along the inner curvature of the aorta where complex spatiotemporal profiles of hemodynamic forces exist and where endothelial cells exhibit a nonpolarized structure and upregulate expression of a provisional matrix enriched in fibronectin and fibrinogen. The regional heterogeneity in endothelial phenotype and matrix expression suggests that lesion progression requires transduction of mechanical cues associated with hemodynamic wall shear stress and artery wall stretch into biochemical signals for inflammation. Integrins have been proposed as candidate mechanotransducers capable of differentiating both physical cues and matrix composition, but an integrinmediated mechanism that confers directionality in response to shear stress has remained elusive. In this issue of Circulation Research, Goldfinger et al1 report that shear stress activates protein kinase A (PKA) to phosphorylate α4 integrin locally at the downstream edge of endothelial cells, and phosphorylated α4 releases inhibition of the GTPase Rac1 to direct polarized reorganization of the cytoskeleton. The proposed mechanism is important not only because it improves understanding of intracellular spatial organization in mechanotransduction mechanisms but also because it suggests new avenues for engineering a healthy endothelium after bypass grafting or vascular stent procedures.