Neovessel formation promotes liver fibrosis via providing latent transforming growth factor-β

Kotaro Sakata, Satoshi Eda, Eun Seo Lee, Mitsuko Hara, Masaya Imoto, Soichi Kojima

Research output: Contribution to journalArticlepeer-review

23 Citations (Scopus)

Abstract

Aim Hepatic fibrosis and angiogenesis occur in parallel during the progression of liver disease. Fibrosis promotes angiogenesis via inducing vascular endothelial growth factor (VEGF) from the activated hepatic stellate cells (HSCs). In turn, increased neovessel formation causes fibrosis, although the underlying molecular mechanism remains undetermined. In the current study, we aimed to address a role of endothelial cells (ECs) as a source of latent transforming growth factor (TGF)-β, the precursor of the most fibrogenic cytokine TGF-β. Methods After recombinant VEGF was administered to mice via the tail vein, hepatic angiogenesis and fibrogenesis were evaluated using immunohistochemical and biochemical analyses in addition to investigation of TGF-β activation using primary cultured HSCs and liver sinusoidal ECs (LSECs). Results In addition to increased hepatic levels of CD31 expression, VEGF-treated mice showed increased α-smooth muscle actin (α-SMA) expression, hepatic contents of hydroxyproline, and latency associated protein degradation products, which reflects cell surface activation of TGF-β via plasma kallikrein (PLK). Liberating the PLK-urokinase plasminogen activator receptor complex from the HSC surface by cleaving a tethering phosphatidylinositol linker with its specific phospholipase C inhibited the activating latent TGF-β present in LSEC conditioned medium and subsequent HSC activation. Conclusion Neovessel formation (angiogenesis) accelerates liver fibrosis at least in part via provision of latent TGF-β that activated on the surface of HSCs by PLK, thereby resultant active TGF-β stimulates the activation of HSCs.

Original languageEnglish
Pages (from-to)950-956
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume443
Issue number3
DOIs
Publication statusPublished - 2014 Jan 17

Keywords

  • Hepatic stellate cells
  • Liver fibrosis
  • Liver sinusoidal endothelial cells
  • Transforming growth factor-β

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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