Impaired extracellular matrix degradation in aortic vessels of cirrhotic rats.
OBJECTIVE
Thinning of the vascular wall occurs in conductance vessels of cirrhotic rats. Increased nitric oxide synthase (NOS) activity has been involved in the pathogenesis of this phenomenon. Therefore, we assessed the NO-regulated cell signaling pathways participating in vascular remodeling in cirrhosis.


METHODS
Aortas were obtained from 15 control and 15 cirrhotic rats. Phosphorylated p38 MAPK and ERK1/2 were used to evaluate the activation of cell MAPK signaling pathways. Extracellular matrix (ECM) turnover was estimated by measuring matrix metalloproteinases (MMPs) activity and protein expression of collagen IV, MMP-2, MMP-9 and tissue inhibitor of MMPs (TIMP)-2. Thereafter, 12 control and 12 cirrhotic rats received Nomega-nitro-L-arginine-methyl-ester or vehicle daily for 11 weeks.


RESULTS
Cirrhotic vessels showed a reduction in ERK1/2 phosphorylation, lower MMP activity, decreased MMPs expression and higher collagen IV and TIMP-2 abundance, compared to control rats. Chronic NOS inhibition normalized ERK1/2 phosphorylation and MMPs activity, increased MMPs abundance and decreased TIMP-2 expression in cirrhotic rats.


CONCLUSIONS
Vascular remodeling in cirrhotic rats is mediated by down-regulation of cell growth and impaired ERK1/2 activation and subsequent imbalance of ECM turnover. These results further stress the importance of vascular NO overactivity in the reduction of vascular wall thickness in cirrhosis.
Fernández-Varo
Guillermo
G
Department of Biochemistry and Molecular Genetics, Hospital Clínic Universitari, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.
Morales-Ruiz
Manuel
M
Ros
Josefa
J
Tugues
Sònia
S
Muñoz-Luque
Javier
J
Casals
Gregori
G
Arroyo
Vicente
V
Rodés
Juan
J
Jiménez
Wladimiro
W
D000818:Animals; D001011:Aorta / Q000378:metabolism* / Q000473:pathology*; D017209:Apoptosis; D002251:Carbon Tetrachloride; D024141:Collagen Type IV / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism* / Q000473:pathology*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000150:complications / Q000473:pathology*; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D024141:Collagen Type IV; D019716:Tissue Inhibitor of Metalloproteinase-2; D002251:Carbon Tetrachloride; D019001:Nitric Oxide Synthase; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D020782:Matrix Metalloproteinases