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Previously, we demonstrated that transient receptor potential channel V4 (TRPV4) could form a functional complex with other proteins to mediate vasodilation in endothelial cells (ECs). But how TRPV4 interacts with the NO pathway in larger arteries requires further exploration.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>We used single\u2010cell RNA\u2010sequencing to find the CD106<jats:sup>+<\/jats:sup> TRPV4<jats:sup>high<\/jats:sup>NOS3<jats:sup>high<\/jats:sup> ECs. The TRPV4\u2013eNOS interaction was verified by co\u2010immunoprecipitation and immuno\u2010FRET, and their binding site was found by site\u2010directed mutagenesis. Endothelium\u2010specific TRPV4 knockout (TRPV4<jats:sub>EC<\/jats:sub><jats:sup>\u2212\/\u2212<\/jats:sup>) mice were used to study the effect of the TRPV4\u2013eNOS interaction on BP. A small molecule, JNc\u2010463, was designed through molecular docking technology.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>We uncovered CD106<jats:sup>+<\/jats:sup> TRPV4<jats:sup>high<\/jats:sup>NOS3<jats:sup>high<\/jats:sup> ECs in the mouse aorta, which could regulate vasodilation via a TRPV4\u2013eNOS interaction, and were essential to regulate BP. The TRPV4\u2013eNOS interaction markedly decreased during the process of hypertension. We further attempted to identify molecules involved in the TRPV4\u2013eNOS interaction and developed a small\u2010molecule drug, JNc\u2010463, which could increase the TRPV4\u2013eNOS interaction to enhance vasodilation and exert antihypertensive effects in mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>This is the first study integrating single\u2010cell RNA\u2010Seq, single\u2010cell functional study and drug screening in aorta. We identified a subpopulation of CD106<jats:sup>+<\/jats:sup> TRPV4<jats:sup>high<\/jats:sup>NOS3<jats:sup>high<\/jats:sup> ECs, in which an impaired TRPV4\u2013eNOS interaction was important in the progress of hypertension, and we designed a small molecule, JNc\u2010463, to improve the impaired TRPV4\u2013eNOS interaction in hypertension.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.15755","type":"journal-article","created":{"date-parts":[[2021,11,25]],"date-time":"2021-11-25T18:57:02Z","timestamp":1637866622000},"page":"2297-2312","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Endothelial TRPV4\u2013<scp>eNOS<\/scp> coupling as a vital therapy target for treatment of hypertension"],"prefix":"10.1111","volume":"179","author":[{"given":"Aiqin","family":"Mao","sequence":"first","affiliation":[{"name":"Wuxi School of Medicine Jiangnan University  Wuxi 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