4.7 Article

Lymphatic vascular integrity is disrupted in type 2 diabetes due to impaired nitric oxide signalling

期刊

CARDIOVASCULAR RESEARCH
卷 107, 期 1, 页码 89-97

出版社

OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvv117

关键词

Permeability; Barrier function

资金

  1. National Heart, Lung, and Blood Institute at the National Institutes of Health [K99 HL124142, R01 HL089784, R01 HL120867, P01 HL095486, R01 HL085119]

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Aims 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. Methods and results 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 (db/db) mice was elevated >30-fold. Augmenting nitric oxide (NO) production by suffusion of L-arginine rescued this defect. Using pharmacological tools and eNOS(-/-) mice, we found that NO increased WT lymphatic permeability, but reduced db/db lymphatic permeability. These conflicting actions of NO were reconciled by the finding that phosphodiesterase 3 (PDE3), normally inhibited by NO signalling, was active in db/db lymphatics and inhibition of this enzyme restored barrier function. Conclusion 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.

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