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Vascular endothelial growth factor and angiopoietin-2 play a major role in the pathogenesis of vascular leakage in cirrhotic rats
  1. Pedro Melgar-Lesmes (melgarpedro{at}yahoo.com)
  1. Biochemistry and Molecular Genetics Service, Hospital Clinic de Barcelona, Spain
    1. Sonia Tugues (stugues{at}hotmail.com)
    1. Biochemistry and Molecular Genetics Service, Hospital Clinic de Barcelona, Spain
      1. Josefa Ros (jrosb{at}ub.edu)
      1. Biochemistry and Molecular Genetics Service, Hospital Clinic de Barcelona, Spain
        1. Guillermo Fernandez-Varo (guillermo.fernandez.varo{at}gmail.com)
        1. Biochemistry and Molecular Genetics Service, Hospital Clinic de Barcelona, Spain
          1. Manuel Morales-Ruiz (morales{at}clinic.ub.es)
          1. Biochemistry and Molecular Genetics Service, Hospital Clinic de Barcelona, Spain
            1. Joan Rodes (jrodes{at}clinic.ub.es)
            1. Liver Unit, Hospital Clinic de Barcelona, Spain
              1. Wladimiro Jimenez (wjimenez{at}clinic.ub.es)
              1. Biochemistry and Molecular Genetics Service, Hospital Clinic de Barcelona, Spain

                Abstract

                Background and aims: The extent and molecular mechanisms governing plasma extravasation and ascites formation in cirrhosis are unknown. VEGF-A and 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 visualized with the Evans Blue and colloidal carbon techniques, respectively. VEGF-A and Ang-2 expression were determined by RT-PCR, immunohistochemistry and Western blot. The effect on vascular permeability induced by VEGFR2 blockade was assessed by the 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 VEGFR2 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.

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