Liver Regeneration Is an Angiogenesis- Associated Phenomenon

Drixler, Tom A.; Vogten, Mathys J.; Ritchie, Ewan D.; Vroonhoven, Theo J. M. V. van; Gebbink, Martijn F.B.G.; Voest, Emile E.; Rinkes, Inne H.M. Borel

doi:10.1097/00000658-200212000-00002

Cited by 128 publications

(92 citation statements)

References 43 publications

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“…Tissue repair and regeneration are partially mediated by angiogenesis (11,33,34). Here we show that the role of the endothelium extends beyond neovascularization to include the endothelial paracrine effect of EETs on tissue regeneration.…”

Section: Discussionmentioning

confidence: 69%

Epoxyeicosanoids promote organ and tissue regeneration

Panigrahy

Kalish

Huang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

128

124

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Epoxyeicosatrienoic acids (EETs), lipid mediators produced by cytochrome P450 epoxygenases, regulate inflammation, angiogenesis, and vascular tone. Despite pleiotropic effects on cells, the role of these epoxyeicosanoids in normal organ and tissue regeneration remains unknown. EETs are produced predominantly in the endothelium. Normal organ and tissue regeneration require an active paracrine role of the microvascular endothelium, which in turn depends on angiogenic growth factors. Thus, we hypothesize that endothelial cells stimulate organ and tissue regeneration via production of bioactive EETs. To determine whether endothelial-derived EETs affect physiologic tissue growth in vivo, we used genetic and pharmacological tools to manipulate endogenous EET levels. We show that endothelial-derived EETs play a critical role in accelerating tissue growth in vivo, including liver regeneration, kidney compensatory growth, lung compensatory growth, wound healing, corneal neovascularization, and retinal vascularization. Administration of synthetic EETs recapitulated these results, whereas lowering EET levels, either genetically or pharmacologically, delayed tissue regeneration, demonstrating that pharmacological modulation of EETs can affect normal organ and tissue growth. We also show that soluble epoxide hydrolase inhibitors, which elevate endogenous EET levels, promote liver and lung regeneration. Thus, our observations indicate a central role for EETs in organ and tissue regeneration and their contribution to tissue homeostasis.

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Section: Discussionmentioning

confidence: 69%

Epoxyeicosanoids promote organ and tissue regeneration

Panigrahy

Kalish

Huang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

128

124

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“…47 Although HGF has been shown to increase the expression of Bclxl, 48 an anti-apoptotic protein, levels of activated caspace 3 and 7 were decreased in the MMP-9 Ϫ/Ϫ mice, and the overall rates of apoptosis were also decreased in these animals. If HGF levels are decreased, one would anticipate decreased levels of the anti-apoptotic protein, Bcl-xl, and therefore increased levels of apoptosis; this is in contrast to what was actually observed in this study.…”

Section: Discussionmentioning

confidence: 99%

Matrix metalloproteinase-9 is an important factor in hepatic regeneration after partial hepatectomy in mice

et al. 2006

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Partial hepatectomy triggers hepatocyte proliferation, hepatic matrix remodeling, and hepatocyte apoptosis, all of which are important processes in the regenerating liver. Previous studies have shown an increase in the levels of matrix metalloproteinases gelatinase A (MMP-2) and gelatinase B (MMP-9) after partial hepatectomy. The goal of this study was to investigate the role of MMP-9 in liver regeneration after partial hepatectomy. A 70% hepatectomy or sham laparotomy was performed in wild-type or MMP-9 -deficient (MMP-9 ؊/؊ ) mice. Hepatic regeneration was determined by liver weight/total body weight ratios and BrdU staining, which was used to a calculate mitotic index at several times postoperatively. Cytokine and growth factor expression was evaluated by Luminex™ bead-based ELISA and Western blots. Finally, the effect of MMP-9 on apoptosis was measured using TUNEL and caspase expression. The MMP-9 ؊/؊ animals had a delayed hepatic regenerative response when compared with wild-type controls. The MMP-9 -deficient animals expressed significantly less VEGF, HGF, and TNF-␣ between days 2 and 3 post-hepatectomy. Apoptosis, as measured by TUNEL staining and caspase expression, was decreased in the MMP-9 ؊/؊ . In conclusion, MMP-9 plays an important role in liver regeneration after partial hepatectomy by affecting matrix remodeling, as well as cytokine, growth factor, and caspase expression.

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“…Hepatocellular production of VEGF leads to maximal levels 48-72 h after partial hepatectomy, and this can increase the dilatation and permeability of blood vessels. Inhibition of angiogenesis by angiostatin impairs both angiogenesis and liver regeneration [109][110][111] . Another approach to inhibit tumor proliferation and angiogenesis has been suggested through blockade of the renin-angiotensin system (RAS) [112] .…”

Section: Trendsmentioning

confidence: 99%

Effect of liver regeneration on malignant hepatic tumors

Shi

Line

2014

WJG

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Liver regeneration after major surgery may activate occult micrometastases and facilitate tumor growth, leading to liver tumor recurrence. Molecular changes during liver regeneration can provide a microenvironment that stimulates intrahepatic tumor propagation through alterations in cellular signaling pathways, where activation and proliferation of mature hepatocytes, hepatic progenitor cells, non-parenchymal liver cells might favor both liver regeneration and tumor growth. This review highlights recent advances of tumor growth and development in the regenerating liver, possible mechanisms and clinical implications. Key words: Hepatocellular carcinoma; Colorectal cancer; Recurrence; Liver regeneration; Hepatic progenitor cell; Epithelial to mesenchymal transition Core tip: The liver has a unique capacity for regeneration after cellular damage or partial removal of tissue, and modern liver surgery relies on this property. Liver regeneration is a complex process involving a large array of growth factors, cytokines and cells to restore hepatic mass and function. Experimental and clinical data indicate that the regeneration signals facilitate the growth of both primary and secondary liver tumors and can alter their malignant potential. This is an important mechanism underlying recurrence after liver surgery. New therapeutic strategies founded on better insight into the relationship between liver regeneration and tumor biology are needed.Shi JH, Line PD. Effect of liver regeneration on malignant hepatic tumors.

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Liver Regeneration Is an Angiogenesis- Associated Phenomenon

Cited by 128 publications

References 43 publications

Epoxyeicosanoids promote organ and tissue regeneration

Epoxyeicosanoids promote organ and tissue regeneration

Matrix metalloproteinase-9 is an important factor in hepatic regeneration after partial hepatectomy in mice

Effect of liver regeneration on malignant hepatic tumors

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