KCNQ5 controls perivascular adipose tissue-mediated vasodilation

Tsvetkov, D.; Schleifenbaum, J.; Wang, Y.; Kassmann, M.; Polovitskaya, M.; Schütze, S.; Rothe, M.; Luft, F. C.; Jentsch, T. J.; Gollasch, M.

doi:10.1101/2023.07.26.550617

bioRxiv · 10.1101/2023.07.26.550617

KCNQ5 controls perivascular adipose tissue-mediated vasodilation

Tsvetkov, D.·Schleifenbaum, J.·Wang, Y.·Kassmann, M.·Polovitskaya, M.·Schütze, S.·Rothe, M.·Luft, F. C.·Jentsch, T. J.·Gollasch, M.

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Abstract

BackgroundSmall arteries exhibit resting tone, a partially contracted state that maintains arterial blood pressure. In arterial smooth muscle cells (SMCs), potassium channels control contraction and relaxation. Perivascular adipose tissue (PVAT) has been shown to exert anticontractile effects on the blood vessels. However, the mechanisms by which PVAT signals small arteries, and their relevance, remain largely unknown. We aimed to uncover key molecular components in adipose-vascular coupling. MethodsA wide-spectrum of genetic mouse models targeting Kcnq3, Kcnq4 and Kcnq5 genes (Kcnq3-/-, Kcnq4-/-, Kcnq5-/-, Kcnq5dn/dn, Kcnq4-/-/Kcnq5dn/dn, Kcnq4-/-/Kcnq5-/-), telemetry blood pressure measurements, targeted lipidomics, and RNA-Seq profiling, wire-myography, patch-clamp, and sharp-electrode membrane potential measurements were used. ResultsWe show that PVAT causes SMC KCNQ5 (KV7.5) channels to hyperpolarize the membrane potential. This effect relaxes small arteries and regulates blood pressure. Oxygenation of polyunsaturated fats generates oxylipins, a superclass of lipid mediators. We identified numerous oxylipins released by PVAT that potentiate vasodilatory action in small arteries by opening SMC KCNQ5 channels. ConclusionsOur results reveal a key molecular function of KCNQ5 channels in adipose-vascular coupling, translating PVAT signals, particularly oxylipins, to the central physiological function of vasoregulation. This novel pathway opens new therapeutic perspectives.

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Tsvetkov, D., Schleifenbaum, J., Wang, Y., Kassmann, M., Polovitskaya, M., Schütze, S., Rothe, M., Luft, F. C., Jentsch, T. J., Gollasch, M.. 2023-07-28. KCNQ5 controls perivascular adipose tissue-mediated vasodilation. https://doi.org/10.1101/2023.07.26.550617

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