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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\u00a0&amp;gt;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.<\/jats:p>","DOI":"10.1093\/function\/zqad017","type":"journal-article","created":{"date-parts":[[2023,4,19]],"date-time":"2023-04-19T01:27:20Z","timestamp":1681867640000},"source":"Crossref","is-referenced-by-count":24,"title":["Lymphatic contractile dysfunction in mouse models of Cant\u00fa Syndrome with KATP channel gain-of-function"],"prefix":"10.1152","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7992-9300","authenticated-orcid":false,"given":"Michael J","family":"Davis","sequence":"first","affiliation":[{"name":"Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine , Columbia MO 65212 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge A","family":"Castorena-Gonzalez","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Tulane University School of Medicine , New Orleans LA 70112 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hae Jin","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine , Columbia MO 65212 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine , Columbia MO 65212 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Remedi","sequence":"additional","affiliation":[{"name":"Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine , St. Louis, MO 63110 , USA"},{"name":"Division of Endocrinology, Diabetes 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