With the goal of effectively treating hypertension and cutting down on the accompanying adverse effects due to systemic activation of target, we explored the mechanism of hypertension caused by dysregulated endothelial TRPV4‐KCa2.3 interaction in small resistance arteries; we also identified a possible therapeutic small molecule that repairs impaired endothelial TRPV4‐KCa2.3 interaction but did not systematically change TRPV4 and KCa2.3 activity. Here, KCNN3 is linked to Hypertension.