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Kir6.1‐dependent K ATP channels in lymphatic smooth muscle and vessel dysfunction in mice with Kir6.1 gain‐of‐function
Author(s) -
Davis Michael J.,
Kim Hae Jin,
Zawieja Scott D.,
CastorenaGonzalez Jorge A.,
Gui Peichun,
Li Min,
Saunders Brian T.,
Zinselmeyer Bernd H.,
Randolph Gwendalyn J.,
Remedi Maria S.,
Nichols Colin G.
Publication year - 2020
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jp279612
Subject(s) - pinacidil , lymphatic system , sulfonylurea receptor , glibenclamide , activator (genetics) , potassium channel , chemistry , microbiology and biotechnology , anatomy , biology , biophysics , endocrinology , biochemistry , receptor , immunology , diabetes mellitus
Key points Spontaneous contractions are essential for normal lymph transport and these contractions are exquisitely sensitive to the K ATP channel activator pinacidil. K ATP channel Kir6.1 and SUR2B subunits are expressed in mouse lymphatic smooth muscle (LSM) and form functional K ATP 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 K ATP 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 K ATP channel GoF offers an explanation for the lymphoedema observed in patients with Cantú 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 K ATP channel subunits in distinct lymphatic cell types, and assess the consequences of altered K ATP channel activity on lymphatic pump function. K ATP 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 K ATP 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 K ATP 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 K ATP 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 K ATP 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 Cantú syndrome, a disorder caused by gain‐of‐function mutations in genes encoding Kir6.1/SUR2.