WNK kinase is a vasoactive chloride sensor in endothelial cells

Area of Science:

• Physiology
• Molecular Biology
• Vascular Biology

Background:

• Endothelial cells (ECs) regulate blood flow and pressure.
• Intracellular chloride (Cl-) and With-No-Lysine (WNK) kinase are present in ECs.
• Their role in EC function and arterial contractility is not fully understood.

Purpose of the Study:

• To investigate if intracellular Cl- signaling in ECs regulates arterial contractility.
• To examine the signaling mechanisms, including WNK kinase, involved in this process.

Main Methods:

• Two-photon microscopy and cell-specific inducible knockout mice were used.
• High-speed lightsheet microscopy captured four-dimensional intracellular Ca2+ signaling.
• Assays measured chloride concentration and WNK kinase activity.

Main Results:

• Acetylcholine induced a rapid decrease in intracellular Cl- concentration ([Cl-]i) in ECs via TMEM16A channel activation.
• TMEM16A activation led to WNK kinase activation, phosphorylating SPAK and OSR1.
• OSR1 potentiated TRPV4 currents, increasing intracellular Ca2+ and causing vasodilation.

Conclusions:

• TMEM16A channel activation reduces [Cl-]i, activating WNK kinase in ECs.
• WNK kinase phosphorylates OSR1, which stimulates TRPV4 channels, leading to vasodilation.
• This pathway involving TMEM16A, WNK kinase, and TRPV4 regulates EC function and arterial contractility.