Our results demonstrate that similar to humans, all four cardiovascular NOX isoforms, including NOX5, are expressed in porcine coronary smooth muscle (CSM) and NOX5-derived ROS are required for growth factor-induced KCNN4 upregulation, providing a novel link between NOX5, CSMC phenotypic modulation, and atherosclerosis. Here, NOX5 is linked to atherosclerosis.