title: EPAC1 promotes adaptive responses in human arterial endothelial cells subjected to low levels of laminar fluid shear stress: Implications in flow-related endothelial dysfunction.
abstract: Blood flow-associated fluid shear stress (FSS) dynamically regulates the endothelium's ability to control arterial structure and function. While arterial endothelial cells (AEC) subjected to high levels of laminar FSS express a phenotype resistant to vascular insults, those exposed to low levels of laminar FSS, or to the FSS associated with oscillatory blood flow, are less resilient. Despite numerous reports highlighting how the cAMP-signaling system controls proliferation, migration and permeability of human AECs (HAECs), its role in coordinating HAEC responses to FSS has received scant attention. Herein we show that the cAMP effector EPAC1 is required for HAECs to align and elongate in the direction of flow, and for the induction of several anti-atherogenic and anti-thrombotic genes associated with these events. Of potential therapeutic importance, EPAC1 is shown to play a dominant role the in response of HAECs to low levels of laminar FSS, such as would be found within atherosclerosis-prone areas of the vasculature. Moreover, we show that EPAC1 promotes these HAEC responses to flow by regulating Vascular Endothelial Growth Factor Receptor-2 and Akt activation, within a VE-cadherin (VECAD)/PECAM1-based mechanosensor. We submit that these findings are consistent with the novel proposition that promoting EPAC1-signaling represents a novel means through which to promote expression of an adaptive phenotype in HAECs exposed to non-adaptive FSS-encoded signals as a consequence of vascular disease.
authors.affiliation: Department of Pathology & Molecular Medicine Queen's University, Kingston, ON K7P3N6, Canada.
authors.forename: Sarah N
authors.initials: SN
authors.lastname: Rampersad
authors.affiliation: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON K7P3N6, Canada.
authors.forename: Silja I
authors.initials: SI
authors.lastname: Freitag
authors.affiliation: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON K7P3N6, Canada.
authors.forename: Fabien
authors.initials: F
authors.lastname: Hubert
authors.affiliation: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON K7P3N6, Canada.
authors.forename: Paulina
authors.initials: P
authors.lastname: Brzezinska
authors.affiliation: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON K7P3N6, Canada.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Butler
authors.affiliation: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON K7P3N6, Canada.
authors.forename: M Bibiana
authors.initials: MB
authors.lastname: Umana
authors.affiliation: Department of Pathology & Molecular Medicine Queen's University, Kingston, ON K7P3N6, Canada.
authors.forename: Alie R
authors.initials: AR
authors.lastname: Wudwud
authors.affiliation: Department of Pathology & Molecular Medicine Queen's University, Kingston, ON K7P3N6, Canada; Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON K7P3N6, Canada. Electronic address: mauriced@queensu.ca.
authors.forename: Donald H
authors.initials: DH
authors.lastname: Maurice
mesh_terms: D000222:Adaptation, Physiological; D001158:Arteries / Q000166:cytology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism* / Q000503:physiopathology; D015870:Gene Expression; D020662:Guanine Nucleotide Exchange Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D040542:Mechanotransduction, Cellular; D013314:Stress, Mechanical
chemical_list: D020662:Guanine Nucleotide Exchange Factors; C116122:RAPGEF3 protein, human
keywords: EPAC1; Fluid shear stress; Human arterial endothelial cells