Kir6.1‐dependent K ATP channels in lymphatic smooth muscle and vessel dysfunction in mice with Kir6.1 gain‐of‐function
Autor: | Colin G. Nichols, Brian Saunders, Hae Jin Kim, Michael J. Davis, Bernd H. Zinselmeyer, Maria S. Remedi, Gwendalyn J. Randolph, Scott D. Zawieja, Jorge A. Castorena-Gonzalez, Peichun Gui, Min Li |
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Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
Membrane potential endocrine system Electrical impedance myography Physiology government.form_of_government Hyperpolarization (biology) Cell biology Contractility 03 medical and health sciences chemistry.chemical_compound Lymphatic Endothelium Electrophysiology 030104 developmental biology 0302 clinical medicine Lymphatic system chemistry Pinacidil cardiovascular system government 030217 neurology & neurosurgery |
Zdroj: | The Journal of Physiology. 598:3107-3127 |
ISSN: | 1469-7793 0022-3751 |
Popis: | Key points Spontaneous contractions are essential for normal lymph transport and these contractions are exquisitely sensitive to the KATP channel activator pinacidil. KATP channel Kir6.1 and SUR2B subunits are expressed in mouse lymphatic smooth muscle (LSM) and form functional KATP channels as verified by electrophysiological techniques. Global deletion of Kir6.1 or SUR2 subunits results in severely impaired lymphatic contractile responses to pinacidil. Smooth muscle-specific expression of Kir6.1 gain-of-function mutant (GoF) subunits results in profound lymphatic contractile dysfunction and LSM hyperpolarization that is partially rescued by the KATP inhibitor glibenclamide. In contrast, lymphatic endothelial-specific expression of Kir6.1 GoF has essentially no effect on lymphatic contractile function. The high sensitivity of LSM to KATP channel GoF offers an explanation for the lymphoedema observed in patients with Cantu syndrome, a disorder caused by gain-of-function mutations in genes encoding Kir6.1 or SUR2, and suggests that glibenclamide may be an appropriate therapeutic agent. Abstract This study aimed to understand the functional expression of KATP channel subunits in distinct lymphatic cell types, and assess the consequences of altered KATP channel activity on lymphatic pump function. KATP channel subunits Kir6.1 and SUR2B were expressed in mouse lymphatic muscle by PCR, but only Kir6.1 was expressed in lymphatic endothelium. Spontaneous contractions of popliteal lymphatics from wild-type (WT) (C57BL/6J) mice, assessed by pressure myography, were very sensitive to inhibition by the SUR2-specific KATP channel activator pinacidil, which hyperpolarized both mouse and human lymphatic smooth muscle (LSM). In vessels from mice with deletion of Kir6.1 (Kir6.1-/- ) or SUR2 (SUR2[STOP]) subunits, contractile parameters were not significantly different from those of WT vessels, suggesting that basal KATP channel activity in LSM is not an essential component of the lymphatic pacemaker, and does not exert a strong influence over contractile strength. However, these vessels were >100-fold less sensitive than WT vessels to pinacidil. Smooth muscle-specific expression of a Kir6.1 gain-of-function (GoF) subunit resulted in severely impaired lymphatic contractions and hyperpolarized LSM. Membrane potential and contractile activity was partially restored by the KATP channel inhibitor glibenclamide. In contrast, lymphatic endothelium-specific expression of Kir6.1 GoF subunits had negligible effects on lymphatic contraction frequency or amplitude. Our results demonstrate a high sensitivity of lymphatic contractility to KATP channel activators through activation of Kir6.1/SUR2-dependent channels in LSM. In addition, they offer an explanation for the lymphoedema observed in patients with Cantu syndrome, a disorder caused by gain-of-function mutations in genes encoding Kir6.1/SUR2. |
Databáze: | OpenAIRE |
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