Endothelial cell PKD2 (TPP1) channels are essential for flow‐mediated vasodilation

Abstract

The endothelium detects shear stress generated by blood flow and transduces this mechanosensory signal to regulate arterial function. Intravascular flow stimulates an increase in arterial diameter, a process termed flow‐mediated vasodilation. The underlying mechanisms by which endothelial function is regulated by flow are poorly understood. Endothelial cells (ECs) express several non‐selective cation channels, including PKD2 (also termed TRPP1), but their involvement in flow‐mediated vasodilation is unclear. Here, we generated novel inducible, endothelial cell‐specific PKD2 knockout (PKD2endo−/−) mice to examine the functional significance of this channel in flow‐mediated vasodilation in resistance‐size mesenteric arteries. Immunofluorescence in intact arteries confirmed that PKD2 was present in endothelial cells of PKD2fl/fl mice, but absent in endothelial cells of PKD2endo−/− mice. Pressure (80 mmHg)‐ and depolarization (60 mM K+)‐induced vasoconstriction and passive diameter were similar in PKD2fl/fl and PKD2endo−/− arteries. In contrast, vasodilation to intravascular flow (15 dyn/cm2) in PKD2endo−/− arteries was ~20 % of that in PKD2fl/fl arteries. Endothelium denudation abolished flow‐mediated vasodilation. L‐NNA, a nitric oxide synthase (NOS) inhibitor, reduced flow‐mediated vasodilation by ~30% in PKD2fl/fl arteries. In contrast, TRAM 34 and apamin, IK and SK channel blockers respectively, did not alter flow‐mediated vasodilation. Microelectrodes were used to measure the membrane potential of pressurized, myogenic arteries. In the absence of luminal flow, the membrane potential of PKD2fl/fl and PKD2endo−/− arteries was similar (~−43 mV). Flow hyperpolarized PKD2fl/fl arteries by ~ 6.8 mV, but PKD2endo−/− arteries by only ~1.2 mV, an attenuation of 82 %. Taken together, our data suggest that flow stimulates PKD2 channels in endothelial cells, leading to membrane hyperpolarization, NOS activation and vasodilation.Support or Funding InformationNIH/NHLBIThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.