Lymphatic vascular integrity is disrupted in type 2 diabetes due to impaired nitric oxide signalling
Identifieur interne : 001B62 ( Main/Exploration ); précédent : 001B61; suivant : 001B63Lymphatic vascular integrity is disrupted in type 2 diabetes due to impaired nitric oxide signalling
Auteurs : Joshua P. Scallan [États-Unis] ; Michael A. Hill [États-Unis] ; Michael J. Davis [États-Unis]Source :
- Cardiovascular Research [ 0008-6363 ] ; 2015.
Abstract
Lymphatic vessel dysfunction is an emerging component of metabolic diseases and can lead to tissue lipid accumulation, dyslipidaemia, and oedema. While lymph leakage has been implicated in obesity and hypercholesterolaemia, whether similar lymphatic dysfunction exists in diabetes has not been investigated.
To measure the lymphatic integrity of transgenic mice, we developed a new assay that quantifies the solute permeability of murine collecting lymphatic vessels. Compared with age-matched wild-type (WT) controls, the permeability of collecting lymphatics from diabetic, leptin receptor-deficient (
In conclusion, we identified the first lymphatic vascular defect in type 2 diabetes, an enhanced permeability caused by low NO bioavailability. Further, this demonstrates that PDE3 inhibition is required to maintain lymphatic vessel integrity and represents a viable therapeutic target for lymphatic endothelial dysfunction in metabolic disease.
Url:
DOI: 10.1093/cvr/cvv117
PubMed: 25852084
PubMed Central: 4490202
Affiliations:
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Hill</name><affiliation wicri:level="1"><nlm:aff id="af1"><addr-line>Department of Medical Pharmacology and Physiology</addr-line>,<institution>University of Missouri</institution>,<addr-line>One Hospital Drive, MA415 Medical Sciences Building, Columbia, MO</addr-line>,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="af2"><addr-line>Dalton Cardiovascular Research Center</addr-line>,<institution>University of Missouri</institution>,<addr-line>Columbia, MO</addr-line>,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Davis, Michael J" sort="Davis, Michael J" uniqKey="Davis M" first="Michael J." last="Davis">Michael J. Davis</name><affiliation wicri:level="1"><nlm:aff id="af1"><addr-line>Department of Medical Pharmacology and Physiology</addr-line>,<institution>University of Missouri</institution>,<addr-line>One Hospital Drive, MA415 Medical Sciences Building, Columbia, MO</addr-line>,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">25852084</idno><idno type="pmc">4490202</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4490202</idno><idno type="RBID">PMC:4490202</idno><idno type="doi">10.1093/cvr/cvv117</idno><date when="2015">2015</date><idno type="wicri:Area/Pmc/Corpus">000262</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000262</idno><idno type="wicri:Area/Pmc/Curation">000262</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000262</idno><idno type="wicri:Area/Pmc/Checkpoint">001107</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">001107</idno><idno type="wicri:Area/Ncbi/Merge">007229</idno><idno type="wicri:Area/Ncbi/Curation">007229</idno><idno type="wicri:Area/Ncbi/Checkpoint">007229</idno><idno type="wicri:doubleKey">0008-6363:2015:Scallan J:lymphatic:vascular:integrity</idno><idno type="wicri:Area/Main/Merge">001B65</idno><idno type="wicri:Area/Main/Curation">001B62</idno><idno type="wicri:Area/Main/Exploration">001B62</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Lymphatic vascular integrity is disrupted in type 2 diabetes due to impaired nitric oxide signalling</title><author><name sortKey="Scallan, Joshua P" sort="Scallan, Joshua P" uniqKey="Scallan J" first="Joshua P." last="Scallan">Joshua P. Scallan</name><affiliation wicri:level="1"><nlm:aff id="af1"><addr-line>Department of Medical Pharmacology and Physiology</addr-line>,<institution>University of Missouri</institution>,<addr-line>One Hospital Drive, MA415 Medical Sciences Building, Columbia, MO</addr-line>,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Hill, Michael A" sort="Hill, Michael A" uniqKey="Hill M" first="Michael A." last="Hill">Michael A. Hill</name><affiliation wicri:level="1"><nlm:aff id="af1"><addr-line>Department of Medical Pharmacology and Physiology</addr-line>,<institution>University of Missouri</institution>,<addr-line>One Hospital Drive, MA415 Medical Sciences Building, Columbia, MO</addr-line>,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="af2"><addr-line>Dalton Cardiovascular Research Center</addr-line>,<institution>University of Missouri</institution>,<addr-line>Columbia, MO</addr-line>,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Davis, Michael J" sort="Davis, Michael J" uniqKey="Davis M" first="Michael J." last="Davis">Michael J. Davis</name><affiliation wicri:level="1"><nlm:aff id="af1"><addr-line>Department of Medical Pharmacology and Physiology</addr-line>,<institution>University of Missouri</institution>,<addr-line>One Hospital Drive, MA415 Medical Sciences Building, Columbia, MO</addr-line>,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></analytic><series><title level="j">Cardiovascular Research</title><idno type="ISSN">0008-6363</idno><idno type="eISSN">1755-3245</idno><imprint><date when="2015">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Aims</title><p>Lymphatic vessel dysfunction is an emerging component of metabolic diseases and can lead to tissue lipid accumulation, dyslipidaemia, and oedema. While lymph leakage has been implicated in obesity and hypercholesterolaemia, whether similar lymphatic dysfunction exists in diabetes has not been investigated.</p></sec><sec><title>Methods and results</title><p>To measure the lymphatic integrity of transgenic mice, we developed a new assay that quantifies the solute permeability of murine collecting lymphatic vessels. Compared with age-matched wild-type (WT) controls, the permeability of collecting lymphatics from diabetic, leptin receptor-deficient (<italic>db/db</italic>) mice was elevated >130-fold. Augmenting nitric oxide (NO) production by suffusion of <sc>l</sc>-arginine rescued this defect. Using pharmacological tools and <italic>eNOS<sup>−/−</sup></italic> mice, we found that NO increased WT lymphatic permeability, but reduced <italic>db/db</italic> lymphatic permeability. These conflicting actions of NO were reconciled by the finding that phosphodiesterase 3 (PDE3), normally inhibited by NO signalling, was active in <italic>db/db</italic> lymphatics and inhibition of this enzyme restored barrier function.</p></sec><sec><title>Conclusion</title><p>In conclusion, we identified the first lymphatic vascular defect in type 2 diabetes, an enhanced permeability caused by low NO bioavailability. Further, this demonstrates that PDE3 inhibition is required to maintain lymphatic vessel integrity and represents a viable therapeutic target for lymphatic endothelial dysfunction in metabolic disease.</p></sec></div></front></TEI><affiliations><list><country><li>États-Unis</li></country></list><tree><country name="États-Unis"><noRegion><name sortKey="Scallan, Joshua P" sort="Scallan, Joshua P" uniqKey="Scallan J" first="Joshua P." last="Scallan">Joshua P. Scallan</name></noRegion><name sortKey="Davis, Michael J" sort="Davis, Michael J" uniqKey="Davis M" first="Michael J." last="Davis">Michael J. Davis</name><name sortKey="Hill, Michael A" sort="Hill, Michael A" uniqKey="Hill M" first="Michael A." last="Hill">Michael A. Hill</name><name sortKey="Hill, Michael A" sort="Hill, Michael A" uniqKey="Hill M" first="Michael A." last="Hill">Michael A. Hill</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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