Intravascular flow stimulates PKD2 (polycystin-2) channels in endothelial cells to reduce blood pressure
PKD2 (polycystin-2, TRPP1), a TRP polycystin channel, is expressed in endothelial cells (ECs), but its physiological functions in this cell type are unclear. 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.
All data generated or analysed during this study are included in the manuscript and supporting files.
Article and author information
National Institutes of Health (HL133256)
- Jonathan H Jaggar
National Institutes of Health (HL137745)
- Jonathan H Jaggar
American Heart Association (16SDG27460007)
- Simon Bulley
American Heart Association (15SDG22680019)
- M Dennis Leo
American Heart Association (20POST35210200)
- Charles E MacKay
American Heart Association (16POST30960010)
- Raquibul Hasan
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: All procedures were approved by the Animal Care and Use Committee of the University of Tennessee (protocol 17-068.0).
- Mark T Nelson, University of Vermont, United States
- Received: March 5, 2020
- Accepted: May 4, 2020
- Accepted Manuscript published: May 4, 2020 (version 1)
- Version of Record published: May 15, 2020 (version 2)
- Version of Record updated: June 30, 2020 (version 3)
© 2020, 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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