title: Adaptive phenotypic modulation of human arterial endothelial cells to fluid shear stress-encoded signals: modulation by phosphodiesterase 4D-VE-cadherin signalling.
abstract: 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.
authors.affiliation: Department of Pathology & Molecular Medicine, Queen's University, Kingston, ON, Canada.
authors.forename: Sarah N
authors.initials: SN
authors.lastname: Rampersad
authors.affiliation: Department of Pathology & Molecular Medicine, Queen's University, Kingston, ON, Canada.
authors.forename: Alie
authors.initials: A
authors.lastname: Wudwud
authors.affiliation: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada.
authors.forename: Fabien
authors.initials: F
authors.lastname: Hubert
authors.affiliation: Department of Pathology & Molecular Medicine, Queen's University, Kingston, ON, Canada; Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada. Electronic address: mauriced@queensu.ca.
authors.forename: Donald H
authors.initials: DH
authors.lastname: Maurice
mesh_terms: D015703:Antigens, CD / Q000378:metabolism*; D001011:Aorta / Q000166:cytology*; D015820:Cadherins / Q000378:metabolism*; D048430:Cell Shape; D000242:Cyclic AMP / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism*; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D007365:Intercellular Junctions / Q000378:metabolism; D040542:Mechanotransduction, Cellular; D010641:Phenotype; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D033081:Shear Strength; D015398:Signal Transduction; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D000242:Cyclic AMP; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D000099152:Cadherin 5; C517376:PDE4D protein, human
keywords: Fluid shear stress; Mechanosensor; Phosphodiesterase 4D; VE-cadherin; Vascular endothelial