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 nonselective 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 ECs. 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.
Highlights
Blood vessels are lined by endothelial cells, which regulate several physiological functions, including contractility, to control regional organ flow and systemic pressure
PC-1-dependent vasodilation occurs over the entire functional shear stress range and via the activation of endothelial nitric oxide synthase
We studied endothelial cell-specific PC-2 knockout (Pkd[2] ecKO) mice and produced PC-1/PC-2 double knockout (Pkd1/Pkd[2] ecKO) mice to investigate whether PC-1 acts in an independent manner or is dependent on PC-2 to respond to physiological stimuli and elicit functional responses
Summary
Blood vessels are lined by endothelial cells, which regulate several physiological functions, including contractility, to control regional organ flow and systemic pressure. Endothelial cells can release several diffusible factors, including nitric oxide (NO), which relaxes arterial smooth muscle cells, leading to vasodilation (1). Endothelial cells electrically couple to smooth muscle cells and directly modulate their membrane potential to modify arterial contractility (2). Substances and mechanical stimuli, such as intravascular flow, are known to act in an endothelial cell-dependent manner to regulate arterial functions. The molecular mechanisms by which these physiological stimuli activate signaling in endothelial cells to modulate vascular contractility are unclear. PC-1 is proposed to act as a mechanical sensor and ligand receptor, stimuli that activate PC-1 and its functional significance are unclear
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