Accumulation of lipid-laden “macrophage foam cell” in the arterial wall is the hallmark of atherosclerosis that leads to the highest number of cardiovascular disease-related deaths in United States. Membrane scavenger receptors such as SR-A, and CD36 play important role in controlling oxidized low-density lipoprotein binding and uptake, and, thereby, in macrophage foam cell formation. Recent studies also put emphasis on the role of mechanical factors, such as matrix stiffness, in the regulation of macrophage function and atherogenesis. However, the identity of a plasma membrane mechanosensor and the underlying mechanisms that may promote atherogenesis is yet to be identified. We have found that a calcium-permeable plasma membrane protein TRPV4, a mechanosensor, may play an essential role in regulating macrophage foam cell formation, a critical process in atherosclerosis. We have also found that TRPV4 is essential for oxLDL uptake, but not for its binding. Altogether, herein, we demonstrate that TRPV4 plays a critical role in macrophage-foam-cell formation by regulating oxLDL uptake in cells.