Hepatocyte growth factor activates endothelial proangiogenic mechanisms relevant in chronic hepatitis C-associated neoangiogenesis.
BACKGROUND
Angiogenesis occurs in inflamed portal tracts of chronic hepatitis C (CHC) patients.


OBJECTIVE
To characterize this phenomenon, by investigating the molecular mechanisms involved in neovessel formation in the livers of CHC patients and the angiogenic effects of hepatocyte growth factor (HGF) on human endothelial cells.


METHODS
Vascular endothelial growth factor (VEGF), VE-cadherin and alphavbeta3 integrin were determined in CHC biopsies by Western blot and immunohistochemistry. Effects of HGF on VEGF and cell adhesion molecules expression by cultured human microvascular endothelial cells were evaluated by Western blot, Northern blot or immunofluorescence. HGF effects on cell proliferation were assessed by [(3)H]thymidine incorporation.


RESULTS
VEGF, VE-cadherin and alphavbeta3 integrin were increased in CHC liver samples. In cultured endothelial cells, HGF transcriptionally increased VEGF expression, an effect which was blocked by an anti-VEGF receptor antibody. HGF transiently decreased VE-cadherin expression and its associated cytoskeleton-linking molecule beta-catenin, thus weakening intercellular contacts. HGF increased alphavbeta3 integrin at focal contacts, and cell proliferation, an effect which was inhibited by an anti-VEGF receptor antibody.


CONCLUSIONS
Our results show that HGF and VEGF modulate the expression of cell adhesion and migration molecules and induce proliferation in endothelial cells, mechanisms through which these factors may contribute to CHC-associated liver angiogenesis.
Medina
Jesús
J
Liver Unit (planta 3), Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, Diego de León 62, E-28006 Madrid, Spain.
Caveda
Luis
L
Sanz-Cameno
Paloma
P
Arroyo
Alicia G
AG
Martín-Vílchez
Samuel
S
Majano
Pedro L
PL
García-Buey
Luisa
L
Sánchez-Madrid
Francisco
F
Moreno-Otero
Ricardo
R
D000328:Adult; D015703:Antigens, CD; D001706:Biopsy; D015820:Cadherins / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D019698:Hepatitis C, Chronic / Q000378:metabolism* / Q000473:pathology; D017228:Hepatocyte Growth Factor / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D007365:Intercellular Junctions / Q000187:drug effects; D008297:Male; D008833:Microcirculation; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000099152:Cadherin 5
D015703:Antigens, CD; D015820:Cadherins; D017228:Hepatocyte Growth Factor; D039302:Integrin alphaVbeta3; D042461:Vascular Endothelial Growth Factor A; D000099152:Cadherin 5