Abstract
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.
Highlights
Endothelial cells line the lumen of all blood vessels and regulate multiple functions, including contractility
We have previously shown that intravascular pressure and a1-adrenoceptors activate PKD2 channels in arterial smooth muscle cells of different organs, leading to depolarization, vasoconstriction and an increase in systemic blood pressure (Bulley et al, 2018)
Genomic PCR confirmed that tamoxifen stimulated Pkd2 recombination in mesenteric arteries of Pkd2fl/fl:Cdh5-creERT2 mice, but not in arteries of Pkd2fl/fl mice (Figure 1—figure supplement 1)
Summary
Endothelial cells line the lumen of all blood vessels and regulate multiple functions, including contractility. Evidence suggests that endothelial cell TRPA1, TRPC3, TRPC4, TRPV1 and TRPV3 channels modulate vascular contractility (Liu et al, 2006; Gao et al, 2012; Freichel et al, 2001; Yang et al, 2010; Bratz et al, 2008; Earley et al, 2010; Sullivan et al, 2015) In many of these previous studies, TRP channel expression and or function was reported in endothelial cells of ex vivo vasculature that does not control systemic blood pressure, including conduit vessels, cerebral arteries, mammary arteries and umbilical vein (Earley and Brayden, 2015; Gao et al, 2012). PKD2 channels are a major contributor to functional flow-sensing in endothelial cells
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