Key result
KCNQ5 channels in smooth muscle cells mediate perivascular adipose tissue-induced vasodilation by responding to PVAT-derived oxylipins, thereby regulating arterial tone and blood pressure.
Why the study?
Perivascular adipose tissue exerts anticontractile effects on blood vessels, but the mechanisms by which it signals small arteries and their relevance remain largely unknown.
PVAT releases oxylipins that induce vasodilation and regulate blood pressure by opening KCNQ5 channels in smooth muscle cells, revealing a novel adipose-vascular coupling mechanism.
Background Small 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. Methods A wide-spectrum of genetic mouse models targeting Kcnq3, Kcnq4 and Kcnq5 genes ( Kcnq3 −/− , Kcnq4 −/− , Kcnq5 −/− , Kcnq5 dn/dn , Kcnq4 −/− /Kcnq5 dn/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. Results We show that PVAT causes SMC KCNQ5 (K V 7.5) 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. Conclusions Our 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 et al. (2023) studied Hypertension. Kcnq5 gene disruption vs. Wild-type mice was evaluated. KCNQ5 channels in smooth muscle cells mediate perivascular adipose tissue-induced vasodilation by responding to PVAT-derived oxylipins, thereby regulating arterial tone and blood pressure.
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