Nuclear VEGFR-2 Expression of Hepatocytes Is Involved in Hepatocyte Proliferation and Liver Regeneration During Chronic Liver Injury

Abstract

Background/Aim: The pathological role of vascular endothelial growth factor receptor 2 (VEGFR-2) in chronic liver injury and liver regeneration is not fully understood. This study analysed the role of VEGFR-2 in liver fibrosis and its regeneration process. Materials and Methods: We administered intraperitoneally 50 mg/kg to 300 mg/kg thioacetamide (TAA) to 9-week-old male mice for 17 weeks. We measured levels of VEGFR-2 protein and identified the location of cells that specifically express VEGFR-2. Results: VEGFR-2 is rarely expressed in normal hepatocytes. However, high VEGFR-2 expression in liver sinusoidal endothelial cells was noted in the TAA group. Conversely, the group that experienced regeneration from liver fibrosis showed significantly higher VEGFR-2 expression in the nucleus of hepatocytes compared to the other groups. Conclusion: VEGFR-2 plays a pivotal role in the nucleus of hepatocytes during liver regeneration and VEGFR-2 may be closely related to cell division. Therefore, VEGFR-2 may be a new therapeutic target for liver regeneration.Liver fibrosis is marked by the formation of an abnormally large amount of scar tissue in the liver (1). Liver fibrosis represents the final common route of chronic liver disease, which eventually leads to cirrhosis (2). Chronic liver disease and cirrhosis result in approximately 35,000 deaths yearly in the United States and cirrhosis is the ninth leading cause of death (3). Therefore, it is very important that liver fibrosis does not progress to cirrhosis, an irreversible stage.Angiogenesis, which is the process of new blood vessel growth from existing vessels, is essential for the physiological functioning of tissues (4). Hepatic angiogenesis is closely associated with the progression of fibrosis in chronic liver diseases (5). According to a recent study, hepatic angiogenesis occurs in chronic liver disease, and is characterized by progressive fibrosis (6). Angiogenesis is a dynamic process regulated by the balance between pro-angiogenic and antiangiogenic factors. Vascular endothelial growth factor (VEGF) is one of the most important pro-angiogenic factors (4).Hepatocytes play a key role in angiogenesis, and have a close anatomical relationship with endothelial cells that secrete VEGF (7). VEGF regulates blood and lymphatic vessel development and maintains homeostasis (8). VEGF is primarily produced by endothelial cells in response to hypoxia and by stimulation of growth factors such as transforming growth factor, interleukins or platelet derived growth factor (9, 10). The biological function of VEGF is mediated upon binding to type III receptor tyrosine kinase (RTK), VEGF receptor 1 (VEGFR-1, Flt-1), VEGFR-2 (KDR/Flk-1), and VEGFR-3 (Flt-4) (11,12). VEGF stimulates angiogenesis by 1473 This article is freely accessible online.

Anlotinib improves bile duct ligature‐induced liver fibrosis in rats via antiangiogenesis regulated by VEGFR2/mTOR pathway

“…Under hypoxia, hepatocytes, endothelial cells, or damaged macrophages release VEGF that binds to the VEGFR on the plasma membrane of endothelial cells, activates a series of intracellular signaling pathways to play a regulatory role, and ultimately promotes angiogenesis (Lee et al, 2021). Angiogenesis is necessary for the physiological regeneration of the liver to form new functional hepatic sinusoids.…”

Effects of a high-carbohydrate high-fat diet on liver morphology in young and old rats

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Glycoprotein non-metastatic melanoma protein B expression correlates with the prognosis of acute liver injury/failure

“…Human monocyte-derived M2c macrophages present Frontiers in Cell and Developmental Biology frontiersin.org significantly higher CD163 expression and slightly higher CD206 expression than M0 macrophages (Spiller et al, 2014;Cutolo et al, 2019). Moreover, M2c macrophages are associated with angiogenesis, especially vascular remodeling, whereas M1 macrophages promote the sprouting of blood vessels via the secretion of vascular endothelial growth factor and TNF-α, which is also required for hepatocyte proliferation (Böhm et al, 2010;Spiller et al, 2014;Lee et al, 2021). Therefore, both M1 and Frontiers in Cell and Developmental Biology frontiersin.org M2 macrophages are necessary for the regeneration of liver tissues.…”