Fluid‐mediated shear stress is an important, but often overlooked, mediator of vascular endothelial cell (VEC) health. VECs in the linear portions of macrovascular structures experience high laminar shear stress and exhibit an anti‐inflammatory and anti‐thrombotic phenotype. However, at vascular bifurcations and large curvatures fluid shear stress dramatically declines. Exposure to this low shear stress reduces VEC expression of vasculoprotective genes, making these areas preferential targets of atherosclerosis development. cAMP‐signaling is known to regulate a diverse array of VEC functions. Using various methodologies, we investigated the role of cAMP, and its downstream effectors, protein kinase A (PKA) and exchange protein activated by cAMP (EPAC)‐1, in regulating VEC health under differential fluid shear stresses. We report a novel role for cAMP, where modulation of this signaling pathway alters the expression of both atheroprotective and inflammatory genes in high and low shear stress conditions. This work has very important therapeutic implications for diseases characterized by endothelial cell dysfunction and atherosclerosis.Grant Funding Source: Canadian Institutes of Health Research