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)-beta, the precursor of the most fibrogenic cytokine TGF-beta. 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-beta 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 alpha-smooth muscle actin (alpha-SMA) expression, hepatic contents of hydroxyproline, and latency associated protein degradation products, which reflects cell surface activation of TGF-beta 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-beta 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-beta that activated on the surface of HSCs by PLK, thereby resultant active TGF-beta stimulates the activation of HSCs. (C) 2013 Elsevier Inc. All rights reserved.