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bioRxiv · 10.1101/2021.10.16.464653

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

Mackay, C. E.·Floen, M.·Leo, M. D.·Hasan, R.·Fernandez-Pena, C.·Singh, P.·Malik, K. U.·Jaggar, J. H.
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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 primarily via the activation of nitric oxide synthase (NOS), with a smaller contribution from small-conductance Ca2+-activated K+ (SK) 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 channel activation, vasodilation and a reduction in blood pressure.

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Mackay, C. E., Floen, M., Leo, M. D., Hasan, R., Fernandez-Pena, C., Singh, P., Malik, K. U., Jaggar, J. H.. 2021-10-16. A plasma membrane-localized polycystin-1/polycystin-2 complex in endothelial cells elicits vasodilation. https://doi.org/10.1101/2021.10.16.464653

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