Ascites from cirrhotic patients induces angiogenesis through the phosphoinositide 3-kinase/Akt signaling pathway
Introduction
Patients with cirrhosis exhibit a characteristic hyperdynamic circulatory syndrome with increased cardiac output and excessive vasodilation, mainly occurring in the splanchnic circulation. Aggravation of these complications marks the progression of compensated cirrhosis into the decompensated phase of the disease characterized by derangement of body fluid homeostasis which results in accumulation of ascites into the peritoneal cavity [1]. Because of its relatively simple composition [2], ascites has generally been considered to have little influence on the hemodynamic, and host defense abnormalities occurring in cirrhotic patients. This concept, however, has recently been challenged by several investigations describing significant amounts of proinflammatory cytokines, growth factors, vasoactive agents or extracellular matrix-forming proteins in ascites of cirrhotic patients [3], [4], [5], [6]. In addition, several studies have demonstrated that the cellular component of ascites might influence the concentration of these substances [7], [8], [9]. It is of interest that many of the substances found in ascites are able to activate the PI3-kinase/Akt signaling pathway. Akt signaling regulates endothelial NO production, cell migration, and survival in physiological conditions which are all cellular responses that contribute to angiogenesis and maturation of the vascular network. The correct adaptation of the vascular system to the activation of this signaling pathway is essential to maintain normal tissue function and homeostasis in response to physiological and pathophysiological stimuli, such as an increase in growth factors and cytokine concentration [10], [11], [12], [13], [14].
In this context, little is known about the pathophysiological adaptation of the endothelium to the presence of ascitic fluid and how these modifications produce long-term structural changes in the splanchnic vasculature. Here, we considered the hypothesis that, under proper stimulus, the production of these substances in the peritoneal cavity could, theoretically, regulate angiogenesis in the splanchnic vascular bed. Therefore, we undertook the present study to investigate the changes in molecular and cellular events caused by the exposure of human endothelial cells to ascites from cirrhotic patients.
Section snippets
Patients
The investigation was performed in ascites of 13 cirrhotic patients (9 women and 4 men). The etiology of cirrhosis was alcoholic in six subjects, HBsAg or hepatitis C antibody-associated in five, both alcoholic and viral in one and cryptogenic in one case. All patients had advanced liver cirrhosis: six belonged to Child-Pugh class B and seven to Child-Pugh class C. Patients developing spontaneous bacterial peritonitis and/or hepatocellular carcinoma were excluded from the study. Ascites from
Ascites activates Erk-1/2, JNK and Akt in endothelial cells
We propose as a working hypothesis that ascites from cirrhotic patients contains bioactive factors that may stimulate distinct intracellular signaling pathway in endothelial cells. To test this hypothesis, we examined phosphorylated and total Erk-1/2 mitogen-activated protein kinase (MAPK), c-Jun N-terminal protein kinase (JNK) MAPK, and Akt upon stimulation of endothelial cells with ascites. Stimulation of BAECs with ascites-induced time-dependent activation of Erk-1/2 MAPK and JNK MAPK which
Discussion
Here we demonstrated that ascites from cirrhotic patients is a bioactive fluid that induces time-dependent activation of Erk-1/2 MAPK, JNK MAPK and Akt signaling pathways in endothelial cells. In addition, we showed that ascites presents in vitro and in vivo angiogenic properties. By contrast, PD fluid lacked angiogenic properties although after long-term peritoneal dialysis the peritoneum of patients with end-stage renal failure undergoes histological changes that include increased
Acknowledgements
The authors thank Dr Kenneth Walsh for kindly providing the AA-Akt adenoviruses as well as Dr A Arañó (from the Centro de Investigación y Desarrollo Aplicado, S.A.L.) for his assistance with the CAM assay. We also thank the staff of Granja Bellavista S.C.P. for providing fertilized 4-day-old eggs and Dr T Doñate for her assistance with peritoneal dialysis patients.
This work was supported by grants from Dirección General de Investigación Científica y Técnica (SAF2001-2585 to M.M-R; and
References (29)
- et al.
The management of ascites in cirrhosis: report on the consensus conference of the International Ascites Club
Hepatology
(2003) - et al.
Increased production of vascular endothelial growth factor in peritoneal macrophages of cirrhotic patients with spontaneous bacterial peritonitis
Hepatology
(2001) - et al.
Akt down-regulation of p38 signaling provides a novel mechanism of vascular endothelial growth factor-mediated cytoprotection in endothelial cells
J Biol Chem
(2001) - et al.
Akt-mediated phosphorylation of the G protein-coupled receptor EDG-1 is required for endothelial cell chemotaxis
Mol Cell
(2001) - et al.
Sphingosine 1-phosphate activates Akt, nitric oxide production, and chemotaxis through a Gi protein/phosphoinositide 3-kinase pathway in endothelial cells
J Biol Chem
(2001) - et al.
Effect of bacterial lipopolysaccharide on endothelin-1 production in human vascular endothelial cells
J Hepatol
(1997) - et al.
Transduction of the liver with activated Akt normalizes portal pressure in cirrhotic rats
Gastroenterology
(2003) - et al.
Akt mediates cytoprotection of endothelial cells by vascular endothelial growth factor in an anchorage-dependent manner
J Biol Chem
(1999) - et al.
Inflammatory cytokines, angiogenesis, and fibrosis in the rat peritoneum
Am J Pathol
(2002) - et al.
Toward better dialysis compatibility: advances in the biochemistry and pathophysiology of the peritoneal membranes
Kidney Int
(2002)
Laminin-10/11 and fibronectin differentially prevent apoptosis induced by serum removal via phosphatidylinositol 3-kinase/Akt- and MEK1/ERK-dependent pathways
J Biol Chem
Hepatocyte growth factor inhibits anoikis in head and neck squamous cell carcinoma cells by activation of ERK and Akt signaling independent of NFkappa B
J Biol Chem
Anti-VEGF receptor-2 monoclonal antibody prevents portal-systemic collateral vessel formation in portal hypertensive mice
Gastroenterology
Endogenous cannabinoids: a new system involved in the homeostasis of arterial pressure in experimental cirrhosis in the rat
Gastroenterology
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