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Lymphatic contractile dysfunction in mouse models of Cantú Syndrome with KATP channel gain-of-function
Michael J Davis1, Jorge A Castorena-Gonzalez2, Hae Jin Kim1
1Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia MO 65212, USA.
Abstract:
Cantú Syndrome (CS) is an autosomal dominant disorder caused by gain-of-function (GoF) mutations in the Kir6.1 and SUR2 subunits of KATP channels. KATP 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.
Insights
Cantú Syndrome (CS) causes hypotension due to KATP channel mutations. This study reveals that these mutations also impair lymphatic vessel function, explaining lymphedema in CS patients.
Area of Science:
- Cardiovascular Physiology
- Ion Channel Biology
- Lymphatic System Function
Background:
- Cantú Syndrome (CS) is an autosomal dominant disorder linked to KATP channel gain-of-function (GoF) mutations.
- CS is associated with hypotension and cardiovascular complications.
- The mechanism underlying lymphedema in >50% of CS patients remains unknown.
Purpose of the Study:
- To investigate lymphatic contractile dysfunction in mouse models of CS-associated KATP channel mutations.
- To determine if impaired lymphatic function contributes to lymphedema in Cantú Syndrome.
Main Methods:
- Assessment of popliteal lymphatic vessel contractile function using pressure myography in mice with Kir6.1[V65M] and SUR2[A478V]/[R1154Q] mutations.
- In vivo confirmation of lymphatic contractile dysfunction using near-infrared fluorescence microscopy.
- Analysis of lymphatic vessel contraction dynamics, including wave entrainment, conduction speed, and pacemaker activity.
- Evaluation of lymphatic pumping capacity against adverse pressure gradients.
Main Results:
- Heterozygous Kir6.1[V65M] lymphatic vessels showed significantly impaired contractile strength and reduced spontaneous contraction frequency.
- Homozygous SUR2[A478V] vessels exhibited profound ex vivo contractile dysfunction; heterozygous vessels were largely normal.
- All CS-associated genotypes displayed disrupted contraction wave dynamics (entrainment, speed, direction) and impaired pumping against outflow load.
- Lymphatic contractile dysfunction severity correlated with the degree of molecular GoF in Kir6.1 or SUR2.
Conclusions:
- Gain-of-function mutations in KATP channel subunits Kir6.1 and SUR2 cause significant lymphatic contractile dysfunction.
- This dysfunction includes impaired contractility, altered wave propagation, and reduced pumping capacity.
- This study provides the first evidence linking smooth muscle ion channel mutations to lymphatic dysfunction and offers a potential explanation for lymphedema in Cantú Syndrome patients.
