title: Lymphatic vascular integrity is disrupted in type 2 diabetes due to impaired nitric oxide signalling.
abstract: OBJECTIVE
  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.
  
  
  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 >130-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.
  
  
  CONCLUSIONS
  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.
authors: Department of Medical Pharmacology and Physiology, University of Missouri, One Hospital Drive, MA415 Medical Sciences Building, Columbia, MO, USA.
authors: Joshua P
authors: JP
authors: Scallan
authors: Department of Medical Pharmacology and Physiology, University of Missouri, One Hospital Drive, MA415 Medical Sciences Building, Columbia, MO, USA Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO, USA.
authors: Michael A
authors: MA
authors: Hill
authors: Department of Medical Pharmacology and Physiology, University of Missouri, One Hospital Drive, MA415 Medical Sciences Building, Columbia, MO, USA davismj@health.missouri.edu.
authors: Michael J
authors: MJ
authors: Davis
mesh_terms: D000818:Animals; D001120:Arginine / Q000494:pharmacology; D002199:Capillary Permeability; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D005260:Female; D042601:Lymphatic Vessels / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000502:physiology*; D058987:Phosphodiesterase 3 Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D058987:Phosphodiesterase 3 Inhibitors; D009569:Nitric Oxide; D001120:Arginine
keywords: Barrier function; Permeability