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Here, we generated inducible, EC-specific Pkd2 knockout mice to examine vascular functions of PKD2. Data show that a broad range of intravascular flow rates stimulate EC PKD2 channels, producing vasodilation. Flow-mediated PKD2 channel activation leads to calcium influx that activates SK\/IK channels and eNOS serine 1176 phosphorylation in ECs. These signaling mechanisms produce arterial hyperpolarization and vasodilation. In contrast, EC PKD2 channels do not contribute to acetylcholine-induced vasodilation, suggesting stimulus-specific function. EC-specific PKD2 knockout elevated blood pressure in mice without altering cardiac function or kidney anatomy. These data demonstrate that flow stimulates PKD2 channels in ECs, leading to SK\/IK channel and eNOS activation, hyperpolarization, vasodilation and a reduction in systemic blood pressure. Thus, PKD2 channels are a major component of functional flow sensing in the vasculature.<\/jats:p>","DOI":"10.7554\/elife.56655","type":"journal-article","created":{"date-parts":[[2020,5,4]],"date-time":"2020-05-04T08:00:35Z","timestamp":1588579235000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.56655","source":"Crossref","is-referenced-by-count":39,"title":["Intravascular flow stimulates PKD2 (polycystin-2) channels in endothelial cells to reduce blood pressure"],"prefix":"10.7554","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2875-0677","authenticated-orcid":true,"given":"Charles E","family":"MacKay","sequence":"first","affiliation":[{"name":"Department of Physiology University of Tennessee Health Science Center Memphis, Memphis, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M Dennis","family":"Leo","sequence":"additional","affiliation":[{"name":"Department of Physiology University of Tennessee Health Science Center Memphis, 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