In the present study, we demonstrate that: 1) TRPV4 activation by GSK1016790A induces eNOS Ser1177 phosphorylation and activation in vascular ECs partially by activating the CaMKK/AMPK pathway; 2) GSK1016790A-elicted eNOS activation inhibits monocyte adhesion to ECs in vitro and leukocytes rolling in vivo; and 3) GSK1016790A attenuates the development of atherosclerosis in ApoE−/− mice fed a Western diet. This evidence concerns the gene APOE and atherosclerosis.