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Lymphatic contractile dysfunction in mouse models of Cantú Syndrome with K(ATP) channel gain-of-function
Cantú Syndrome (CS) is an autosomal dominant disorder caused by gain-of-function (GoF) mutations in the Kir6.1 and SUR2 subunits of K(ATP) channels. K(ATP) overactivity results in a chronic reduction in arterial tone and hypotension, leading to other systemic cardiovascular complications. However, t...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10194823/ https://www.ncbi.nlm.nih.gov/pubmed/37214333 http://dx.doi.org/10.1093/function/zqad017 |
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author | Davis, Michael J Castorena-Gonzalez, Jorge A Kim, Hae Jin Li, Min Remedi, Maria Nichols, Colin G |
author_facet | Davis, Michael J Castorena-Gonzalez, Jorge A Kim, Hae Jin Li, Min Remedi, Maria Nichols, Colin G |
author_sort | Davis, Michael J |
collection | PubMed |
description | Cantú Syndrome (CS) is an autosomal dominant disorder caused by gain-of-function (GoF) mutations in the Kir6.1 and SUR2 subunits of K(ATP) channels. K(ATP) overactivity results in a chronic reduction in arterial tone and hypotension, leading to other systemic cardiovascular complications. However, the underlying mechanism of lymphedema, developed by >50% of CS patients, is unknown. We investigated whether lymphatic contractile dysfunction occurs in mice expressing CS mutations in Kir6.1 (Kir6.1[V65M]) or SUR2 (SUR2[A478V], SUR2[R1154Q]). Pressure myograph tests of contractile function of popliteal lymphatic vessels over the physiological pressure range revealed significantly impaired contractile strength and reduced frequency of spontaneous contractions at all pressures in heterozygous Kir6.1[V65M] vessels, compared to control littermates. Contractile dysfunction of intact popliteal lymphatics in vivo was confirmed using near-infrared fluorescence microscopy. Homozygous SUR2[A478V] vessels exhibited profound contractile dysfunction ex vivo, but heterozygous SUR2[A478V] vessels showed essentially normal contractile function. However, further investigation of vessels from all three GoF mouse strains revealed significant disruption in contraction wave entrainment, decreased conduction speed and distance, multiple pacemaker sites, and reversing wave direction. Tests of 2-valve lymphatic vessels forced to pump against an adverse pressure gradient revealed that all CS-associated genotypes were essentially incapable of pumping under an imposed outflow load. Our results show that varying degrees of lymphatic contractile dysfunction occur in proportion to the degree of molecular GoF in Kir6.1 or SUR2. This is the first example of lymphatic contractile dysfunction caused by a smooth muscle ion channel mutation and potentially explains the susceptibility of CS patients to lymphedema. |
format | Online Article Text |
id | pubmed-10194823 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-101948232023-05-19 Lymphatic contractile dysfunction in mouse models of Cantú Syndrome with K(ATP) channel gain-of-function Davis, Michael J Castorena-Gonzalez, Jorge A Kim, Hae Jin Li, Min Remedi, Maria Nichols, Colin G Function (Oxf) Research Article Cantú Syndrome (CS) is an autosomal dominant disorder caused by gain-of-function (GoF) mutations in the Kir6.1 and SUR2 subunits of K(ATP) channels. K(ATP) overactivity results in a chronic reduction in arterial tone and hypotension, leading to other systemic cardiovascular complications. However, the underlying mechanism of lymphedema, developed by >50% of CS patients, is unknown. We investigated whether lymphatic contractile dysfunction occurs in mice expressing CS mutations in Kir6.1 (Kir6.1[V65M]) or SUR2 (SUR2[A478V], SUR2[R1154Q]). Pressure myograph tests of contractile function of popliteal lymphatic vessels over the physiological pressure range revealed significantly impaired contractile strength and reduced frequency of spontaneous contractions at all pressures in heterozygous Kir6.1[V65M] vessels, compared to control littermates. Contractile dysfunction of intact popliteal lymphatics in vivo was confirmed using near-infrared fluorescence microscopy. Homozygous SUR2[A478V] vessels exhibited profound contractile dysfunction ex vivo, but heterozygous SUR2[A478V] vessels showed essentially normal contractile function. However, further investigation of vessels from all three GoF mouse strains revealed significant disruption in contraction wave entrainment, decreased conduction speed and distance, multiple pacemaker sites, and reversing wave direction. Tests of 2-valve lymphatic vessels forced to pump against an adverse pressure gradient revealed that all CS-associated genotypes were essentially incapable of pumping under an imposed outflow load. Our results show that varying degrees of lymphatic contractile dysfunction occur in proportion to the degree of molecular GoF in Kir6.1 or SUR2. This is the first example of lymphatic contractile dysfunction caused by a smooth muscle ion channel mutation and potentially explains the susceptibility of CS patients to lymphedema. Oxford University Press 2023-04-18 /pmc/articles/PMC10194823/ /pubmed/37214333 http://dx.doi.org/10.1093/function/zqad017 Text en © The Author(s) 2023. Published by Oxford University Press on behalf of American Physiological Society. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Article Davis, Michael J Castorena-Gonzalez, Jorge A Kim, Hae Jin Li, Min Remedi, Maria Nichols, Colin G Lymphatic contractile dysfunction in mouse models of Cantú Syndrome with K(ATP) channel gain-of-function |
title | Lymphatic contractile dysfunction in mouse models of Cantú Syndrome with K(ATP) channel gain-of-function |
title_full | Lymphatic contractile dysfunction in mouse models of Cantú Syndrome with K(ATP) channel gain-of-function |
title_fullStr | Lymphatic contractile dysfunction in mouse models of Cantú Syndrome with K(ATP) channel gain-of-function |
title_full_unstemmed | Lymphatic contractile dysfunction in mouse models of Cantú Syndrome with K(ATP) channel gain-of-function |
title_short | Lymphatic contractile dysfunction in mouse models of Cantú Syndrome with K(ATP) channel gain-of-function |
title_sort | lymphatic contractile dysfunction in mouse models of cantú syndrome with k(atp) channel gain-of-function |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10194823/ https://www.ncbi.nlm.nih.gov/pubmed/37214333 http://dx.doi.org/10.1093/function/zqad017 |
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