Adaptive phenotypic modulation of human arterial endothelial cells to fluid shear stress-encoded signals: modulation by phosphodiesterase 4D-VE-cadherin signalling
| Autor: | Sarah N. Rampersad, Donald H. Maurice, Fabien Hubert, Alie Wudwud |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Biology CREB Mechanotransduction Cellular Adherens junction 03 medical and health sciences Antigens CD Cyclic AMP Humans Cell Shape Protein kinase B Aorta Gene knockdown Endothelial Cells Phosphodiesterase Cell Biology Cadherins Vascular Endothelial Growth Factor Receptor-2 Phenotype Cyclic Nucleotide Phosphodiesterases Type 4 Cell biology Platelet Endothelial Cell Adhesion Molecule-1 Intercellular Junctions 030104 developmental biology Gene Expression Regulation Gene Knockdown Techniques Immunology KLF2 biology.protein VE-cadherin Shear Strength Signal Transduction |
| Zdroj: | Cellular Signalling. 28:741-748 |
| ISSN: | 0898-6568 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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