title: Increased nitric oxide production in lymphatic endothelial cells causes impairment of lymphatic drainage in cirrhotic rats.
abstract: OBJECTIVE
  The lymphatic network plays a major role in maintaining tissue fluid homoeostasis. Therefore several pathological conditions associated with oedema formation result in deficient lymphatic function. However, the role of the lymphatic system in the pathogenesis of ascites and oedema formation in cirrhosis has not been fully clarified. The aim of this study was to investigate whether the inability of the lymphatic system to drain tissue exudate contributes to the oedema observed in cirrhosis.
  
  
  METHODS
  Cirrhosis was induced in rats by CCl(4) inhalation. Lymphatic drainage was evaluated using fluorescent lymphangiography. Expression of endothelial nitric oxide synthase (eNOS) was measured in primary lymphatic endothelial cells (LyECs). Inhibition of eNOS activity in cirrhotic rats with ascites (CH) was carried out by L-N(G)-methyl-L-arginine (L-NMMA) treatment (0.5 mg/kg/day).
  
  
  RESULTS
  The (CH) rats had impaired lymphatic drainage in the splanchnic and peripheral regions compared with the control (CT) rats. LyECs isolated from the CH rats showed a significant increase in eNOS and nitric oxide (NO) production. In addition, the lymphatic vessels of the CH rats showed a significant reduction in smooth muscle cell (SMC) coverage compared with the CT rats. CH rats treated with L-NMMA for 7 days showed a significant improvement in lymphatic drainage and a significant reduction in ascites volume, which were associated with increased plasma volume. This beneficial effect of L-NMMA inhibition was also associated with a significant increase in lymphatic SMC coverage.
  
  
  CONCLUSIONS
  The upregulation of eNOS in the LyECs of CH rats causes long-term lymphatic remodelling, which is characterised by a loss of SMC lymphatic coverage. The amelioration of this lymphatic abnormality by chronic eNOS inhibition results in improved lymphatic drainage and reduced ascites.
authors.affiliation: Department of Biochemistry and Molecular Genetics, Hospital Clinic Universitari, Villarroel 170, Barcelona 08036, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Ribera
authors.forename: Montse
authors.initials: M
authors.lastname: Pauta
authors.forename: Pedro
authors.initials: P
authors.lastname: Melgar-Lesmes
authors.forename: Sònia
authors.initials: S
authors.lastname: Tugues
authors.forename: Guillermo
authors.initials: G
authors.lastname: Fernández-Varo
authors.forename: Kara F
authors.initials: KF
authors.lastname: Held
authors.forename: Guadalupe
authors.initials: G
authors.lastname: Soria
authors.forename: Raúl
authors.initials: R
authors.lastname: Tudela
authors.forename: Anna M
authors.initials: AM
authors.lastname: Planas
authors.forename: Carlos
authors.initials: C
authors.lastname: Fernández-Hernando
authors.forename: Vicente
authors.initials: V
authors.lastname: Arroyo
authors.forename: Wladimiro
authors.initials: W
authors.lastname: Jiménez
authors.forename: Manuel
authors.initials: M
authors.lastname: Morales-Ruiz
mesh_terms: D000818:Animals; D001201:Ascites / Q000209:etiology; D015415:Biomarkers / Q000378:metabolism; D002251:Carbon Tetrachloride; D042783:Endothelial Cells / Q000378:metabolism*; D004729:Endothelium, Lymphatic / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000503:physiopathology*; D008208:Lymphatic System / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D008220:Lymphography; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D019323:omega-N-Methylarginine / Q000378:metabolism
chemical_list: D015415:Biomarkers; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D002251:Carbon Tetrachloride; D019001:Nitric Oxide Synthase