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Originally published online as doi:10.2353/ajpath.2007.060887 on April 13, 2007

Published online before print April 13, 2007
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(American Journal of Pathology. 2007;170:1942-1953.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.060887

Proangiogenic Cytokines as Hypoxia-Dependent Factors Stimulating Migration of Human Hepatic Stellate Cells

Erica Novo*, Stefania Cannito*, Elena Zamara*, Lorenzo Valfrè di Bonzo*, Alessandra Caligiuri{dagger}, Carlo Cravanzola*, Alessandra Compagnone*, Sebastiano Colombatto*, Fabio Marra{dagger}, Massimo Pinzani{dagger} and Maurizio Parola*

From the Dipartimento Medicina e Oncologia Sperimentale,* Università di Torino, Torino; and the Dipartimento Medicina Interna,{dagger} Centro di Ricerca, Trasferimento e Alta Formazione "DENOTHE," Università di Firenze, Firenze, Italy

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.






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Copyright © 2007 by the American Society for Investigative Pathology.