Hypoxia‐inducible factor‐1α expression in experimental cirrhosis: correlation with vascular endothelial growth factor expression and angiogenesis

Abstract

Angiogenesis progresses together with fibrogenesis during chronic liver injury. Hypoxia-inducible factor-1alpha (HIF-1alpha), a master regulator of homeostasis, plays a pivotal role in hypoxia-induced angiogenesis through its regulation of vascular endothelial growth factor (VEGF). The association between hypoxia, angiogenesis and VEGF expression has been demonstrated in experimental cirrhosis. However, expression of HIF-1alpha has yet to be reported. The aim of this study was to investigate the significance of HIF-1alpha expression during experimental liver fibrosis and the relationships between HIF-1alpha expression, VEGF expression and angiogenesis. Cirrhosis was induced in male Wistar rats by intraperitoneal administration of diethyl nitrosamine (DEN) (100 mg/kg, once a week). The serial sections from liver tissues were stained with anti-HIF-1alpha, anti-VEGF and anti-CD34 antibodies before being measured by light microscopy. Our results showed that HIF-1alpha expression gradually increases according to the severity of fibrosis (p<0.01). Moreover, its expression was found to be correlated with angiogenesis (r=0.916) and VEGF expression (r=0.969). The present study demonstrates that HIF-1alpha might have a role in the development of angiogenesis via regulation of VEGF during experimental liver fibrogenesis and suggests that this factor could be a potential target in the manipulation of angiogenesis in chronic inflammatory diseases of the liver.

Comparison of Hypoxia-inducible Factor-1α Expression before and after Transcatheter Arterial Embolization in Rabbit VX2 Liver Tumors

“…They also evaluated the HIF-1 α levels 2hrs post- TAE as compared to our study where the post-TAE biopsies were taken at 10 min. In another recent study, Bozova et al (10) showed that in an experimental liver fibrogenesis model in Wistar rats, HIF-1 α expression gradually increased as the severity of cirrhosis increased and correlated strongly with the VEGF expression and angiogenesis. We are unaware of any published studies which have evaluated HIF-1 α expression within the same tumor before and after TAE / TACE.…”

“…In 1992, Semenza et al (8) discovered that Hypoxia inducible Factor-1 α (HIF-1 α) was a control factor regulating the subsequent release of multiple angiogenic factors (Figure 1) (9), including Vascular Endothelial Growth Factor (VEGF), basic fibroblast growth factor (bFGF) and insulin like growth factor (IGF). During TAE, stasis to forward blood flow creates hypoxic conditions and may promote tumor angiogenesis (6, 10) by inducing expression of HIF-1 α (11). …”

The role of chemokines in acute and chronic hepatitis C infection

“…134 In fact, blood vessel density and VEGF expression correlate directly with Child-Pugh score and the proliferative index, size and grade of HCC tumours. [135][136][137][138][139][140] A number of chemokines and their receptors are upregulated in the diseased liver and peripheral blood in the progression of liver fibrosis to cirrhosis and in the pathogenesis of malignant HCC. These molecules regulate inflammation, fibroproliferation, angiogenesis, carcinogenesis, metastasis, and anti-tumour immunity.…”

Hepatitis C virus core protein upregulates the expression of vascular endothelial growth factor via the nuclear factor‐κB/hypoxia‐inducible factor‐1α axis under hypoxic conditions

“…This discrepancy might be derived from differences in HCV‐related materials and/or the cell lines used. In the present study, it is worth noting that NS5A, another potentially oncogenic protein of HCV, 10,11 did not induce HIF‐1α upregulation under hypoxia, suggesting that HCV core protein contributes more to hepatocarcinogenesis under hypoxia via angiogenesis, a fundamental biological event in the microenvironment of cirrhotic liver 5,6 …”

“…In cirrhotic livers, blood supply is impaired as a consequence of fibrosis, which induces a hypoxic microenvironment in the liver 5 . Indeed, a previous study demonstrates that the expression level of hypoxia‐inducible factor‐1α (HIF‐1α), a nuclear transcription factor, gradually increases with the degree of fibrosis 6 . Under normoxic conditions, HIF‐1α is proline hydroxylated by HIF hydroxylase, resulting in degradation via the ubiquitin‐proteasomal pathway, which involves von Hippel‐Lindau (VHL) protein.…”