The structure and function of blood vessels adapt to environmental changes such as physical development and exercise^,,. This phenomenon is based on the ability of the endothelial cells to sense and respond to blood flow^,,; however, the underlying mechanisms remain unclear. Here we show that the ATP-gated P2X4 ion channel^,, expressed on endothelial cells and encoded by P2rx4 in mice, has a key role in the response of endothelial cells to changes in blood flow. P2rx4^−/− mice do not have normal endothelial cell responses to flow, such as influx of Ca²⁺ and subsequent production of the potent vasodilator nitric oxide (NO). Additionally, vessel dilation induced by acute increases in blood flow is markedly suppressed in P2rx4^−/− mice. Furthermore, P2rx4^−/− mice have higher blood pressure and excrete smaller amounts of NO products in their urine than do wild-type mice. Moreover, no adaptive vascular remodeling, that is, a decrease in vessel size in response to a chronic decrease in blood flow, was observed in P2rx4^−/− mice. Thus, endothelial P2X4 channels are crucial to flow-sensitive mechanisms that regulate blood pressure and vascular remodeling.