biostudies-literatureMacKay CEAmerican Heart AssociationNHLBI NIH HHSNational Heart, Lung, and Blood InstituteMedical Research Councile74765https://www.ebi.ac.uk/biostudies/studies/S-EPMC8933003biostudies-literatureUnknown11Polycystin-1 (PC-1, PKD1), a receptor-like protein expressed by the <i>Pkd1</i> gene, is present in a wide variety of cell types, but its cellular location, signaling mechanisms, and physiological functions are poorly understood. Here, by studying tamoxifen-inducible, endothelial cell (EC)-specific <i>Pkd1</i> knockout (<i>Pkd1</i> ecKO) mice, we show that flow activates PC-1-mediated, Ca²⁺-dependent cation currents in ECs. EC-specific PC-1 knockout attenuates flow-mediated arterial hyperpolarization and vasodilation. PC-1-dependent vasodilation occurs over the entire functional shear stress range and via the activation of endothelial nitric oxide synthase (eNOS) and intermediate (IK)- and small (SK)-conductance Ca²⁺-activated K⁺ channels. EC-specific PC-1 knockout increases systemic blood pressure without altering kidney anatomy. PC-1 coimmunoprecipitates with polycystin-2 (PC-2, PKD2), a TRP polycystin channel, and clusters of both proteins locate in nanoscale proximity in the EC plasma membrane. Knockout of either PC-1 or PC-2 (<i>Pkd2</i> ecKO mice) abolishes surface clusters of both PC-1 and PC-2 in ECs. Single knockout of PC-1 or PC-2 or double knockout of PC-1 and PC-2 (<i>Pkd1</i>/<i>Pkd2</i> ecKO mice) similarly attenuates flow-mediated vasodilation. Flow stimulates nonselective cation currents in ECs that are similarly inhibited by either PC-1 or PC-2 knockout or by interference peptides corresponding to the C-terminus coiled-coil domains present in PC-1 or PC-2. In summary, we show that PC-1 regulates arterial contractility through the formation of an interdependent signaling complex with PC-2 in ECs. Flow stimulates PC-1/PC-2 clusters in the EC plasma membrane, leading to eNOS, IK channel, and SK channel activation, vasodilation, and a reduction in blood pressure.eLifeA plasma membrane-localized polycystin-1/polycystin-2 complex in endothelial cells elicits vasodilation.PMC8933003MR/M024962/1R01 HL158846HL149662R01 HL019134R01 HL133256R01 HL149662R01 HL137745MC_EX_MR/N50192X/1855946HL137745HL155180Hl155186HL133256HL19134R01 HL15518020POST35210200Hasan RFernandez-Pena CLeo MDMacKay CEFloen MSingh PMalik KUJaggar JHGarrud TACfalseA plasma membrane-localized polycystin-1/polycystin-2 complex in endothelial cells elicits vasodilation.Polycystin-1 (PC-1, PKD1), a receptor-like protein expressed by the <i>Pkd1</i> gene, is present in a wide variety of cell types, but its cellular location, signaling mechanisms, and physiological functions are poorly understood. Here, by studying tamoxifen-inducible, endothelial cell (EC)-specific <i>Pkd1</i> knockout (<i>Pkd1</i> ecKO) mice, we show that flow activates PC-1-mediated, Ca²⁺-dependent cation currents in ECs. EC-specific PC-1 knockout attenuates flow-mediated arterial hyperpolarization and vasodilation. PC-1-dependent vasodilation occurs over the entire functional shear stress range and via the activation of endothelial nitric oxide synthase (eNOS) and intermediate (IK)- and small (SK)-conductance Ca²⁺-activated K⁺ channels. EC-specific PC-1 knockout increases systemic blood pressure without altering kidney anatomy. PC-1 coimmunoprecipitates with polycystin-2 (PC-2, PKD2), a TRP polycystin channel, and clusters of both proteins locate in nanoscale proximity in the EC plasma membrane. Knockout of either PC-1 or PC-2 (<i>Pkd2</i> ecKO mice) abolishes surface clusters of both PC-1 and PC-2 in ECs. Single knockout of PC-1 or PC-2 or double knockout of PC-1 and PC-2 (<i>Pkd1</i>/<i>Pkd2</i> ecKO mice) similarly attenuates flow-mediated vasodilation. Flow stimulates nonselective cation currents in ECs that are similarly inhibited by either PC-1 or PC-2 knockout or by interference peptides corresponding to the C-terminus coiled-coil domains present in PC-1 or PC-2. In summary, we show that PC-1 regulates arterial contractility through the formation of an interdependent signaling complex with PC-2 in ECs. Flow stimulates PC-1/PC-2 clusters in the EC plasma membrane, leading to eNOS, IK channel, and SK channel activation, vasodilation, and a reduction in blood pressure.2022-01-01T00:00:00Z2022 Mar2026-06-04T04:35:46.291Z2024-11-09T12:05:22.313ZS-EPMC89330033522971810.7554/eLife.74765