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Blood vessels are lined by endothelial cells that form a semipermeable barrier to restrict fluid flow across the vessel wall. The endothelial barrier is known to respond to various molecular mechanisms, but the effects of mechanical signals that arise due to blood flow remain poorly understood. Here, we report a microfluidic model that mimics the flow conditions and endothelial/extracellular matrix (ECM) architecture of a vessel bifurcation to enable systematic investigation of how flow dynamics that arise within bifurcating vessels guides the endothelial response to biochemical signals. Applying the strengths of our system, we further investigate the endothelial response to sphingosine-1-phosphate, a bioactive lipid that has demonstrated flow-dependent regulation of vascular permeability. We demonstrate that bifurcated fluid flow (BFF) that arises at the base of vessel bifurcations and laminar shear stress (LSS) that arises along downstream vessel walls induce a decrease in endothelial permeability. Furthermore, we identify that flow-dynamics and chaperone proteins regulate the endothelial response to S1P. Through pharmacological inhibition of S1P receptors 1 and 2, we report ligand-independent mechanical activation of S1P receptors 1 and 2, providing support for the role of G protein-coupled receptors as mechanosensors. These findings introduce BFF as an important regulator of vascular permeability, and establish flow dynamics as a determinant of the endothelial response to S1P.