CAMP‐signaling via EPAC1 mediates vascular endothelial cell adaptation to fluid‐shear stress

Abstract

Herein, we report a novel role for cAMP‐signaling in human aortic endothelial cell (HAEC) adaptation to fluid‐mediated shear stress (FSS). Our results showed that increases in cAMP enhanced elongation and alignment of HAECs cultured under LSS for 48hrs and that this effect was largely mediated by the cAMP‐effector molecule, exchange protein activated by cAMP (EPAC)‐1, but not Protein Kinase A (PKA). Additionally, major HAEC cAMP‐hydrolyzing enzyme, phosphodiesterase (PDE)4D, was also shown to play a crucial role in integrating FSS signals in these cells.Our results demonstrated that flow‐mediated increases in atheroprotective genes, Kruppel‐like factor, endothelial nitric oxide synthase and thrombomodulin mRNA expression were reduced in EPAC‐1 and PDE4D knockdown HAECs exposed to both LSS and HSS. Furthermore, EPAC‐1 knockdown increased leukocyte extravasation across HAEC monolayers in vitro and activation of EPAC significantly reduced LPS‐induced leukocyte rolling flux in mice.VECs have numerous mechanosensors which facilitate the integration of FSS signals from the flowing blood. One such sensor consists of platelet‐endothelial cell adhesion molecule (PECAM)‐1, vascular endothelial‐cadherin (VECAD) and vascular endothelial growth factor receptor (VEFGR)‐2. Our current data suggests that EPAC1 and PDE4D can additionally mediate flow‐sensing through this mechanosensory complex. All together, this data provides important mechanistic insight providing therapeutic targets in endothelial dysfunction and atherosclerosis.