Vascular endothelial growth factor and angiopoietin-2 play a major role in the pathogenesis of vascular leakage in cirrhotic rats.
OBJECTIVE
The extent and molecular mechanisms governing plasma extravasation and formation of ascites in cirrhosis are unknown. Vascular endothelial growth factor-A (VEGF-A) and angiopoietin-2 (Ang-2) are endogenous substances with powerful vascular permeability effects. We assessed regional blood flow, vascular leakage, mRNA and tissular expression of VEGF-A and Ang-2 and vascular permeability following VEGF receptor 2 blockade in control and cirrhotic rats to define the vascular territories showing altered vascular permeability in cirrhosis and to determine whether VEGF-A and Ang-2 are involved in this phenomenon.


METHODS
Arterial blood flow was analysed with the coloured microsphere method. Vascular leakage was measured and visualised with the dye Evan's Blue and colloidal carbon techniques, respectively. VEGF-A and Ang-2 expression were determined by real-time polymerase chain reaction (RT-PCR), immunohistochemistry and western blot. The effect on vascular permeability induced by VEGFR(2) blockade was assessed by administration of the receptor inhibitor SU11248.


RESULTS
Arterial blood flow was increased in the mesentery, pancreas and small intestine but not in the kidney and spleen of cirrhotic rats as compared to controls. Increased vascular leakage was observed in the mesentery and liver, where colloidal carbon spread from microvessels to the adjacent fibrotic tracts. Increased hepatic and mesenteric expression of VEGF-A and Ang-2 was found in cirrhotic rats as compared to controls. Blockade of VEGFR(2) markedly reduced hepatic and mesenteric vascular leakage in cirrhotic rats.


CONCLUSIONS
Enhanced endothelial permeability is restricted to the hepatic and mesenteric vascular beds in cirrhotic rats with ascites and VEGF-A and Ang-2 are key factors in the signalling pathways regulating this dysfunction.
Melgar-Lesmes
P
P
Biochemistry and Molecular Genetics Service, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain.
Tugues
S
S
Ros
J
J
Fernández-Varo
G
G
Morales-Ruiz
M
M
Rodés
J
J
Jiménez
W
W
D042683:Angiopoietin-1 / Q000032:analysis; D042702:Angiopoietin-2 / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D002244:Carbon; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology; D008099:Liver / Q000098:blood supply / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000378:metabolism*; D008297:Male; D008643:Mesentery / Q000098:blood supply / Q000378:metabolism; D055806:Microvessels; D010179:Pancreas / Q000098:blood supply / Q000378:metabolism; D011205:Povidone; D011758:Pyrroles / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D013194:Staining and Labeling; D000077210:Sunitinib; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000032:analysis / Q000037:antagonists & inhibitors
D042683:Angiopoietin-1; D042702:Angiopoietin-2; D004338:Drug Combinations; D007211:Indoles; D011758:Pyrroles; D012333:RNA, Messenger; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C078073:carbon colloid; D002244:Carbon; D040301:Vascular Endothelial Growth Factor Receptor-2; D011205:Povidone; D000077210:Sunitinib