A plasma membrane‐localized polycystin‐1/polycystin‐2 complex in endothelial cells elicits vasodilation

Abstract

Polycystin‐1 (PC‐1, PKD1), a receptor‐like protein expressed by the Pkd1 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 Pkd1 knockout (Pkd1 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 nitric oxide synthase (NOS) and small‐and intermediate‐conductance Ca2+‐activated K+ (SK/IK) 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 (Pkd2 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 (Pkd1/Pkd2 ecKO mice) similarly attenuates flow‐mediated vasodilation. Flow stimulates non‐selective 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 and demonstrate that this occurs through the formation of an interdependent signaling complex with PC‐2 in endothelial cells. Flow stimulates PC‐1/PC‐2 clusters in the EC plasma membrane, leading to Ca2+ influx, NOS and SK/IK channel activation, vasodilation and a reduction in blood pressure.