Ascites from cirrhotic patients induces angiogenesis through the phosphoinositide 3-kinase/Akt signaling pathway.
OBJECTIVE
Ascites in patients with cirrhosis is associated with worsening of systemic hemodynamics. Thus, the aim of this study was to investigate the biological activity of ascites on endothelial cells.


METHODS
Human umbilical vein endothelial cells (HUVECs) were used to investigate the angiogenic activity of ascites obtained from cirrhotic patients.


RESULTS
Ascites-induced Akt activation, cell migration and tube formation in HUVECs. The pretreatment of HUVECs with the phosphatidylinositide 3-kinase (PI3-kinase) inhibitor LY294002, resulted in a decrease in chemotaxis and cell tube formation induced by ascites. Moreover, the inhibition of Akt activity in HUVECs by transduction of an inactive phosphorylation Akt mutant (AA-Akt), blocked tube formation. These angiogenic effects of ascites were also operative in vivo showing a PI3-kinase activation dependence in the angiogenesis induced by ascites. In addition, the preincubation of ascites with anti-fibronectin antibody led to a significant decrease in HUVECs migration, cell tube formation and in vivo angiogenesis.


CONCLUSIONS
These results confirm the novel concept that ascites is a bioactive fluid which can modify vascular properties through the activation of the PI3-kinase/Akt pathway in endothelial cells. Furthermore, our results demonstrated that this ascites-induced mechanism is mediated, at least in part, by fibronectin.
Morales-Ruiz
Manuel
M
Hormonal Laboratory, Hospital Clínic and Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Villarroel 170 Barcelona 08036, Spain. mmoralesruiz@ub.edu
Tugues
Sònia
S
Cejudo-Martín
Pilar
P
Ros
Josefa
J
Melgar-Lesmes
Pedro
P
Fernández-Llama
Patricia
P
Arroyo
Vicente
V
Rodés
Juan
J
Jiménez
Wladimiro
W
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001201:Ascites / Q000150:complications* / Q000209:etiology / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D002633:Chemotaxis; D002642:Chick Embryo; D042783:Endothelial Cells / Q000201:enzymology; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005353:Fibronectins / Q000276:immunology / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008103:Liver Cirrhosis / Q000150:complications*; D008297:Male; D009389:Neovascularization, Pathologic / Q000209:etiology* / Q000503:physiopathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D015398:Signal Transduction
D000906:Antibodies; D005353:Fibronectins; D019869:Phosphatidylinositol 3-Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases