A plasma membrane-localized polycystin-1/polycystin-2 complex in endothelial cells elicits vasodilation
- University of Tennessee Health Science Center, United States
- University Miguel Hernandez-CSIC, Spain
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 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 (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 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 eNOS, IK channel and SK channel activation, vasodilation and a reduction in blood pressure.
Data availability
All data generated or analyzed during this study are included in the manuscript.
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Author details
Funding
National Heart, Lung, and Blood Institute (HL133256)
- Jonathan H Jaggar
National Heart, Lung, and Blood Institute (HL137745)
- Jonathan H Jaggar
National Heart, Lung, and Blood Institute (HL155180)
- Jonathan H Jaggar
National Heart, Lung, and Blood Institute (Hl155186)
- Jonathan H Jaggar
National Heart, Lung, and Blood Institute (HL19134)
- Kafait U Malik
American Heart Association (20POST35210200)
- Charles E MacKay
American Heart Association (855946)
- Charles E MacKay
National Heart, Lung, and Blood Institute (HL149662)
- M Dennis Leo
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to an approved institutional animal care and use committee (IACUC) protocol (#20-0168) of the University of Tennessee. All surgery was performed under anesthesia, and every effort was made to minimize suffering.
Copyright
© 2022, MacKay et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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A plasma membrane-localized polycystin-1/polycystin-2 complex in endothelial cells elicits vasodilation
eLife 11:e74765.
https://doi.org/10.7554/eLife.74765
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