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Cited by 25Lymphatic System and DiseasesIon channel regulation and functionLymphatic Disorders and Treatments

Lymphatic contractile dysfunction in mouse models of Cantú Syndrome with KATP channel gain-of-function

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Davis, Michael J, Castorena-Gonzalez, Jorge A, Kim, Hae Jin, Li, Min, Remedi, Maria, Nichols, Colin G·2023·Function
DOI 10.1093/function/zqad017PMC PMC10194823
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Abstract

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.

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  • The pump limit may be a more sensitive indicator of contractile dysfunction than frequency, amplitude, and calculated pump flow.

    “Frequency, amplitude, and calculated pump flow are commonly used as indices of LV pumping ability, but another parameter, the pump limit, may be a more sensitive indicator of contractile dysfunction (57).”

    From Transport and Immune Functions of the Lymphatic System. (2025) · cites this paper as [57]

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Cited by

Sorted by citations

Authors
Davis, M. J., Castorena-Gonzalez, J. A., Kim, H. J., Li, M., Remedi, M., & Nichols, C. G.
Affiliations
  • University of Missouri (US)
  • Department of Pharmacology, Tulane University School of Medicine , New Orleans LA 70112 , USA
  • Washington University in St. Louis (US)
Corresponding author
Davis, Michael J
ORCID
Venue
Function
Publisher
American Physiological Society
Published
2023
Volume
4
Issue
3
Pages
zqad017-zqad017
ISSN
2633-8823 (ISSN-L)
DOI
10.1093/function/zqad017
PMC
PMC10194823
OpenAlex
W4366426970
Cited by
25
References
2
Citations by year
2026: 1 · 2025: 11 · 2024: 6 · 2023: 7
FWCI
3.05
Type
journal article
Language
en
Open access
Licence
Locations
  • Function (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institutes of Health (R01 HL-141107, HL-122578, R35 HL-140024)
  • National Research Foundation of Korea (NRF-2020R1A6A3A03037151)
Topics
  • Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
  • Health Sciences › Medicine › Surgery › Lymphatic Disorders and Treatments
Keywords
Cantú syndrome, Kir6.1, SUR2, lymphedema, lymphatic smooth muscle, pressure myography, lymphatic pumping, ion channel mutations
MeSH terms
Gain of Function Mutation, Adenosine Triphosphate, Animals, Cardiomegaly, Hypertrichosis, Mutation, Osteochondrodysplasias, Mice, KATP Channels

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