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首页> 外文期刊>Cellular Signalling >Adaptive phenotypic modulation of human arterial endothelial cells to fluid shear stress-encoded signals: modulation by phosphodiesterase 4D-VE-cadherin signalling
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Adaptive phenotypic modulation of human arterial endothelial cells to fluid shear stress-encoded signals: modulation by phosphodiesterase 4D-VE-cadherin signalling

机译：人动脉内皮细胞对流体剪切应力编码信号的自适应表型调节：磷酸二酯酶4D-VE-钙黏着蛋白信号传导的调节

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Although cAMP-signalling regulates numerous functions of vascular endothelial cells (VECs), including their ability to impact vascular resistance in response to changes in blood flow dynamics, few of the mechanisms underlying these effects have yet to be described. In addition to forming stable adherens junctions (AJs) in static VEC cultures, VE-cadherin (VECAD) has emerged as a critical component in a key mechanosensor responsible for linking altered blood flow dynamics and the VEC-mediated control of vascular resistance. Previously, a cAMP phosphodiesterase, PDE4D, was shown to coordinate the VEC permeability limiting effects of cAMP-elevating agents in human arterial VECs (HAECs). Herein, we report that PDE4D acts to allow cAMP-elevating agents to regulate VECADs' role as a sensor of flow-associated fluid shear stress (FSS)-encoded information in HAECs. Thus, we report that PDE4 activity is increased in HAECs exposed to laminar FSS and that this effect contributes to controlling how FSS impacts the morphological and gene expression changes in HAECs exposed to flow. More specifically, we report that PDE4D regulates the efficiency with which VECAD, within its mechanosensor, controls VEGFR2 and Akt activities. Indeed, we show that PDE4D knockdown (KD) significantly blunts responses of HAECs to levels of FSS characteristically found in areas of the vasculature in which stenosis is prevalent. We propose that this effect may provide a new therapeutic avenue in modulating VEC behaviour at these sites by promoting an adaptive and vasculo-protective phenotype. (C) 2015 Elsevier Inc. All rights reserved.
机译：尽管cAMP信号传导调节血管内皮细胞（VEC）的许多功能，包括它们响应血流动力学变化而影响血管阻力的能力，但尚未阐明引起这些作用的机制。除了在静态VEC培养物中形成稳定的粘附连接（AJ）外，VE-钙粘着蛋白（VECAD）已成为关键机械传感器中的重要组件，该机械传感器负责链接变化的血流动力学和VEC介导的血管阻力控制。以前，已显示出cAMP磷酸二酯酶PDE4D可协调cAMP增强剂在人动脉VEC（HAEC）中的VEC渗透性限制作用。本文中，我们报道PDE4D的作用是使cAMP提升剂调节VECAD作为HAECs中与流相关的流体剪切应力（FSS）编码信息的传感器的作用。因此，我们报告说，暴露于层流FSS的HAEC中PDE4活性增加，并且这种作用有助于控制FSS如何影响暴露于流动的HAEC中的形态和基因表达变化。更具体地说，我们报道PDE4D调节VECAD在其机械传感器内控制VEGFR2和Akt活性的效率。确实，我们显示PDE4D敲低（KD）明显减弱了HAECs对狭窄部位普遍存在的脉管系统区域中特征性FSS水平的反应。我们建议这种作用可能会通过促进适应性和血管保护性表型在调节这些部位的VEC行为中提供新的治疗途径。 （C）2015 Elsevier Inc.保留所有权利。

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