Endothelial nitric oxide synthase is a key mediator of hepatocyte proliferation in response to partial hepatectomy in mice
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UNLABELLED: Endothelial nitric oxide synthase (eNOS) is a critical modulator of vascular tone and blood flow and plays major roles in liver physiology and pathophysiology. Nitric oxide (NO) is widely recognized as one of the key humoral factors important for the initiation of liver regeneration in response to partial hepatectomy. Liver regeneration in response to partial hepatectomy is dependent on the efficiency of growth factor-mediated cell-cycle progression. Epidermal growth factor receptor (EGFR) is a critical mediator of multiple hepatic mitogens, such as epidermal growth factor (EGF), transforming growth factor alpha, amphiregulin, and heparin-binding EGF in regenerating livers. However, the functional significance of endothelial nitric oxide synthase (eNOS) expressed in hepatocytes, and its potential role in EGFR-mediated hepatocyte proliferation, remains unexplored. We sought to determine whether eNOS is essential for hepatocyte proliferation in response to partial hepatectomy (PH). Our studies with eNOS knockout (eNOS(-/-) ) mice suggest that eNOS activation is essential for the efficient induction of early events and elicitation of a robust hepatocyte proliferative response to PH. Moreover, eNOS expression is essential for the efficient early induction of matrix metalloprotease-9, a known mediator of extracellular matrix remodeling and growth factor activation in regenerating livers. Our in vitro studies suggest that eNOS is a critical mediator of EGF-induced hepatocyte proliferation, potentially via its influence on the induction of early growth response-1 (Egr-1) and phosphorylation of c-Jun--known mediators of cell-cycle progression. EGF-induced eNOS phosphorylation at Ser 1177 is dependent on the phosphorylation and activation of EGFR/PI3 kinase/AKT signaling in hepatocytes. CONCLUSION: Collectively, these results highlight a hitherto unrecognized role for eNOS activation in hepatocyte proliferation with implications for targeted therapies to enhance liver regenerative response in chronic disorders.
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NOS3 is expressed at highest relative abundance in vascular endothelium, but is also found in neurons, epithelial cells, cardiomyocytes, adipocytes, and hepatocytes.
“NOS3 (commonly called endothelial NOS or eNOS) is expressed to highest relative abundance in the vascular endothelium, but has also been found in neurons, epithelial cells, and cardiomyocytes [66] as well as adipocytes [67, 68] and hepatocytes [69-71].”
From Regulation of obesity and insulin resistance by nitric oxide (2014) · cites this paper as [69]
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Regulation of obesity and insulin resistance by nitric oxide
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“most abundant in the vascular endothelium, but has also been found in neurons, epithelial cells, and cardiomyocytes [66] as well as adipocytes [67,68] and hepatocytes [69–71].”
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- Authors
- Mei, Y., & Thevananther, S.
- Affiliations
- Baylor College of Medicine (US)
- Corresponding author
- Thevananther, Sundararajah
- Venue
- Hepatology
- Published
- 2011-11
- Volume
- 54
- Issue
- 5
- Pages
- 1777-1789
- ISSN
- 0270-9139 (ISSN-L)
- PMC
- PMC3579770
- OpenAlex
- W2024838891
- Cited by
- 54
- References
- 32
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 7 · 2023: 3 · 2022: 1 · 2020: 3 · 2019: 3 · 2018: 3 · 2017: 4 · 2016: 3 · 2015: 4 · 2014: 10 · 2013: 3 · 2012: 3
- FWCI
- 3.45
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (T32HL007939)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK069558, P30DK056338, T32DK007664)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Surgery › Organ Transplantation Techniques and Outcomes
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Keywords
- endothelial nitric oxide synthase, hepatocyte proliferation, liver regeneration, partial hepatectomy, epidermal growth factor receptor, epidermal growth factor, MMP-9, extracellular matrix remodeling, early growth response 1, c-Jun phosphorylation, PI3K/Akt signaling, eNOS Ser1177 phosphorylation, eNOS knockout mice
- MeSH terms
- Animals, Cell Cycle, Cell Division, Cells, Cultured, Hepatectomy, Liver Regeneration, Male, Mice, Inbred C57BL, Mice, Mutant Strains, Transcription Factor AP-1, Phosphatidylinositol 3-Kinases, Matrix Metalloproteinase 9, MAP Kinase Signaling System, Hepatocytes, Proto-Oncogene Proteins c-akt, Mice, Early Growth Response Protein 1, Nitric Oxide Synthase Type III
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