Proangiogenic cytokines as hypoxia-dependent factors stimulating migration of human hepatic stellate cells.
Pathological angiogenesis is associated with the fibrogenic progression of chronic liver diseases. Experimental data suggest that hypoxia and vascular endothelial growth factor (VEGF) may stimulate proliferation and synthesis of type I collagen in activated, myofibroblast-like rat hepatic stellate cells (HSC/MFs). In this study, we investigated whether hypoxia, recombinant VEGF, or angiopoietin 1 (Ang-1) may affect other crucial profibrogenic features. In human HSC/MFs, which constitutively express VEGF receptor-1 and -2 (VEGFR-1, VEGFR-2) and the Ang-1 receptor Tie-2, exposure to hypoxia, VEGF, or Ang-1 resulted in a Ras/Erk-dependent stimulation of chemokinesis and chemotaxis. Migration of human HSC/MFs under hypoxic conditions involved up-regulation of VEGF-A, Ang-1, and related receptors and was mainly dependent on VEGFR-2 (Flk-1). In specimens from either cirrhotic rat livers or from patients with hepatitis C virus-related cirrhosis, HSC/MFs expressed proangiogenic factors and related receptors in areas of active fibrogenesis (ie, at the leading or lateral edge of developing incomplete fibrotic septa). Data presented herein suggest that VEGF and Ang-1 may contribute to fibrogenesis by acting as hypoxia-inducible, autocrine, and paracrine factors able to recruit myofibroblast-like cells. Moreover, HSC/MFs, in addition to their established profibrogenic role, may also contribute to neoangiogenesis during chronic hepatic wound healing.
Novo
Erica
E
Università degli Studi di Torino, Dipartimento Medicina e Oncologia Sperimentale, Corso Raffaello 30, 10125 Turin, Italy.
Cannito
Stefania
S
Zamara
Elena
E
Valfrè di Bonzo
Lorenzo
L
Caligiuri
Alessandra
A
Cravanzola
Carlo
C
Compagnone
Alessandra
A
Colombatto
Sebastiano
S
Marra
Fabio
F
Pinzani
Massimo
M
Parola
Maurizio
M
D042683:Angiopoietin-1 / Q000378:metabolism*; D000818:Animals; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D003470:Culture Media / Q000378:metabolism; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology; D006526:Hepatitis C / Q000473:pathology; D006801:Humans; D000860:Hypoxia; D008099:Liver / Q000166:cytology* / Q000378:metabolism; D008103:Liver Cirrhosis / Q000378:metabolism / Q000473:pathology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D042787:Receptor, TIE-2 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D014945:Wound Healing
D042683:Angiopoietin-1; D003470:Culture Media; D042461:Vascular Endothelial Growth Factor A; D042787:Receptor, TIE-2; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2