What underlies endothelial shear sensing? The matrix, of course.
What underlies endothelial shear sensing? The matrix, of course.
复制标题
内皮剪切感应的基础是什么？
DOI：
10.1161/circresaha.108.184382
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发表时间：
2008
影响因子：
20.1
通讯作者：
Terada,LanceS
中科院分区：
文献类型：
--
作者：
Terada,LanceS
许多慢性血管疾病优先发生在动脉导管的不同区域，例如颅内动脉瘤，其发生在弯曲区域内或分叉处，以及肺丛状病变，其发生在二分分支点之外。这些形状的几何形状强烈表明，流体动力学在这些病变的发病机制中起着关键作用。早期动脉粥样化长期以来一直被认为是在类似的位置发生的，这些位置预计会经历严重的剪切速率动态扰动，例如流动逆转和分离气泡。人们可能预期内膜和内膜下病变的进展将进一步扭曲剪切分布，导致疾病的传播。因此，动脉粥样硬化可能是最常见的人类疾病的强烈影响的机械信号，可能是许多疾病的机械感觉。剪切激活了哪些途径，如何感知剪切？大多数动脉表面经历层流，其在时间和空间上相对连续。暴露于这种层流的内皮细胞相对静止，并且连续剪切的内皮细胞的转录组显示促进存活的基因的表达和与增殖和炎症相关的基因的抑制。1相反，血流紊乱激活一组炎症、凋亡和促凝血基因，支持异常机械信号的致动脉粥样硬化性质。2在实际的机械传感器下游，许多激酶途径在激活这种广泛的细胞反应中显得很重要，例如细胞外信号调节激酶（ERK）5和AMP激活的蛋白激酶。3，4因为细胞锚自己的底层基质，以抵抗剪切力，整合素或相关的焦点接触蛋白似乎是合理的候选人作为近端mechanosensors。在细胞剪切的数秒内，血小板内皮细胞粘附分子（PECAM）-1和血管内皮生长因子受体-2都变得酪氨酸磷酸化，并且使用磁珠直接牵引PECAM-1也启动PECAM-1磷酸化和ERK信号传导。5，6最近，这2种蛋白质被证明通过VE-钙粘蛋白偶联，作为接头，
Anumber of chronic vascular diseases preferentially arise in distinct zones of arterial conduits such as intracranial aneurysms, which occur inside regions of curvature or at bifurcations, and pulmonary plexiform lesions, which occur just beyond dichotomous branch points. The geometry of these shapes strongly suggests that fluid dynamics play a key role in the pathogenesis of these lesions. Early atheromas have long been known to develop in similar locations, which are predicted to experience severe dynamic perturbations in shear rates such as flow reversal and separation bubbles. One might expect that progression of intimal and subintimal lesions would further distort shear distribution, leading to propagation of the disease. Thus, atherosclerosis is perhaps the most common human disease strongly influenced by mechanical signals, one of perhaps many diseases of mechanosensation. What pathways are activated by shear, and how is this sensed?The majority of arterial surfaces experience laminar flow, which is relatively continuous across time and space. Endothelium exposed to such laminar flow is relatively quiescent, and the transcriptome of continuously sheared endothelium demonstrates expression of genes promoting survival and suppression of genes associated with proliferation and inflammation. 1 Conversely, disturbed flow activates a panel of inflammatory, apoptotic, and procoagulant genes, supporting the atherogenic nature of abnormal mechanical signals. 2 Downstream of the actual mechanosensors, a number of kinase pathways appear important in activating such broad cellular responses, such as extracellular signal-regulated kinase (ERK) 5 and AMP-activated protein kinase. 3, 4 Because cells anchor themselves to the underlying matrix to resist shear forces, integrins or associated focal contact proteins would seem to be logical candidates as proximal mechanosensors. Within seconds of cell shearing, both platelet endothelial cell adhesion molecule (PECAM)-1 and vascular endothelial growth factor receptor-2 become tyrosinephosphorylated, and direct traction on PECAM-1 using magnetic beads also initiates PECAM-1 phosphorylation and ERK signaling. 5, 6 More recently, these 2 proteins were shown to be coupled through VE-cadherin, acting as an adaptor, in a