CoChat
Sign Up
Cited by 66Liver physiology and pathologyAngiogenesis and VEGF in CancerLiver Disease and Transplantation

Neuropilin-1 aggravates liver cirrhosis by promoting angiogenesis via VEGFR2-dependent PI3K/Akt pathway in hepatic sinusoidal endothelial cells

Open access
Wang, Le, Feng, Yuemin, Xie, Xiaoyu, Wu, Hao, Su, Xiao Nan, Qi, Jianni, Xin, Wei, Gao, Lifen +3 more·2019·EBioMedicine
DOI 10.1016/j.ebiom.2019.04.050PMC PMC6558257
Open this paper in CoChat — free account

Abstract

Background We have revealed that neuropilin-1 (NRP-1) promoted hepatic stellate cell activation and liver fibrosis through its profibrogenic signalling pathways. However, the role of NRP-1 in angiogenesis in hepatic sinusoidal endothelial cells (HSECs) during liver cirrhosis remains unclear. Methods The correlation between NRP-1 expression and angiogenesis was evaluated in both human and murine cirrhotic liver tissues by immunohistochemical staining, quantitative real-time PCR, and western blotting. In addition, the role and mechanism of NRP-1 in regulating VEGFR2-dependent angiogenesis was identified in endothelial cells (ECs) in vitro. Moreover, liver histocultures were used to test the therapeutic effect of NRP-1 blocking in liver fibrosis. Findings Higher expression of NRP-1 in HSECs was detected, which was positively correlated with angiogenesis in liver cirrhosis. In vitro, NRP-1 knockdown suppressed the expression and activation of VEGFR2, accompanied by reduced ability of the vascular tube formation and the migration of ECs. Conversely, NRP-1 overexpression upregulated VEGFR2, promoted tube formation, and the migration of ECs. Mechanistically, NRP-1 modulated the expression of VEGFR2 by regulating FAK and its kinase activity. Furthermore, NRP-1 promoted VEGFR2-dependent angiogenesis via the PI3K/Akt pathway in HSECs. Blocking NRP-1 function reduced intrahepatic angiogenesis and fibrosis-associated factors in the in vitro liver histocultures. Interpretation NRP-1 promotes angiogenesis by upregulating the expression and activation of VEGFR2 through the PI3K/Akt signalling pathway in liver cirrhosis. This study highlights the possibility of therapeutically targeting NRP-1 for the treatment of cirrhosis. Fund National Natural Science Foundation of China (No. 81570551; 81770607; 81600469; 81401868), Key Research project of Shandong Province (No. 2016GSF201008; 2017GSF218053), Natural Science Foundation of Shandong Province (No. ZR2017MH102), National Science and Technology Major Project of China (No. 2018ZX10302206-001-006).

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.ebiom.2019.04.050

Cites

2 of 2 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Ssb1 inhibits STAT3 phosphorylation in activated HSC-T6 cells without influencing other possible binding proteins such as PI3K, AKT, and MAPK3.

    “Our study revealed that Ssb1 inhibited STAT3 phosphorylation in the activated HSC‐T6 cells without influencing other possible binding proteins, such as PI3K, AKT, and MAPK3 [48, 49].”

    From Saikosaponin b1 Attenuates Liver Fibrosis by Blocking STAT3/Gli1 Interaction and Inducing Gli1 Degradation (2025) · cites this paper as [49]

    The Results section on NRP-1 and VEGFR2-dependent angiogenesis reports PI3K/Akt phosphorylation in endothelial cells, not the effect of Ssb1 in activated HSC-T6 cells. Searches for Ssb1, STAT3, HSC-T6, and MAPK3 found no passage addressing the claimed inhibition or lack of effect on the other proteins. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 28

  1. [1]Schuppan D. Afdhal N.H. Liver cirrhosis Lancet 371 9615 2008 838 851 18328931 PMC2271178
  2. [2]Iwakiri Y. Shah V. Rockey D.C. Vascular pathobiology in chronic liver disease and cirrhosis - current status and future directions J Hepatol 61 4 2014 912 924 24911462 PMC4346093
  3. [4]Ferrara N. Gerber H.P. LeCouter J. The biology of VEGF and its receptors Nat Med 9 6 2003 669 676 12778165
  4. [5]He Z. Tessier-Lavigne M. Neuropilin is a receptor for the axonal chemorepellent Semaphorin III Cell 90 4 1997 739 751 9288753
  5. [6]Bielenberg D.R. Pettaway C.A. Takashima S. Klagsbrun M. Neuropilins in neoplasms: expression, regulation, and function Exp Cell Res 312 5 2006 584 593 16445911
  6. [7]Bagri A. Tessier-Lavigne M. Watts R.J. Neuropilins in tumor biology Clin Cancer Res 15 6 2009 1860 1864 19240167
  7. [8]Pan Q. Chanthery Y. Liang W.C. Stawicki S. Mak J. Rathore N. Blocking neuropilin-1 function has an additive effect with anti-VEGF to inhibit tumor growth Cancer Cell 11 1 2007 53 67 17222790
  8. [9]Berge M. Allanic D. Bonnin P. de Montrion C. Richard J. Suc M. Neuropilin-1 is upregulated in hepatocellular carcinoma and contributes to tumour growth and vascular remodelling J Hepatol 55 4 2011 866 875 21338642
  9. [10]Cao S. Yaqoob U. Das A. Shergill U. Jagavelu K. Huebert R.C. Neuropilin-1 promotes cirrhosis of the rodent and human liver by enhancing PDGF/TGF-beta signaling in hepatic stellate cells J Clin Invest 120 7 2010 2379 2394 20577048 PMC2898590
  10. [11]Wang L. Zhao X. Feng Y. Ma X. Wu H. Zhu Q. Intrahepatic angiogenesis increases portal hypertension in hepatitis B patients with cirrhosis Hepatol Res 47 3 2017 E94 E103 27115574
  11. [13]Herzog B. Pellet-Many C. Britton G. Hartzoulakis B. Zachary I.C. VEGF binding to NRP1 is essential for VEGF stimulation of endothelial cell migration, complex formation between NRP1 and VEGFR2, and signaling via FAK Tyr407 phosphorylation Mol Biol Cell 22 15 2011 2766 2776 21653826 PMC3145551
  12. [14]Fantin A. Herzog B. Mahmoud M. Yamaji M. Plein A. Denti L. Neuropilin 1 (NRP1) hypomorphism combined with defective VEGF-A binding reveals novel roles for NRP1 in developmental and pathological angiogenesis Development 141 3 2014 556 562 24401374 PMC3899814
  13. [15]Gelfand M.V. Hagan N. Tata A. Oh W.J. Lacoste B. Kang K.T. Neuropilin-1 functions as a VEGFR2 co-receptor to guide developmental angiogenesis independent of ligand binding Elife 3 2014 e03720 PMC4197402 25244320
  14. [16]Murga M. Fernandez-Capetillo O. Tosato G. Neuropilin-1 regulates attachment in human endothelial cells independently of vascular endothelial growth factor receptor-2 Blood 105 5 2005 1992 1999 15522955
  15. [17]Koch S. Claesson-Welsh L. Signal transduction by vascular endothelial growth factor receptors Cold Spring Harb Perspect Med 2 7 2012 a006502 PMC3385940 22762016
  16. [18]Kofler N.M. Simons M. Angiogenesis versus arteriogenesis: neuropilin 1 modulation of VEGF signaling F1000Prime Rep 7 2015 26 25926977 PMC4371373
  17. [19]Ohie S. Udagawa Y. Aoki D. Nozawa S. Histoculture drug response assay to monitor chemoresponse Methods Mol Med 110 2005 79 86 15901929
  18. [20]Sun S. Wu H.J. Guan J.L. Nuclear FAK and its kinase activity regulate VEGFR2 transcription in angiogenesis of adult mice Sci Rep 8 1 2018 2550 29416084 PMC5803223
  19. [21]Taura K. De Minicis S. Seki E. Hatano E. Iwaisako K. Osterreicher C.H. Hepatic stellate cells secrete angiopoietin 1 that induces angiogenesis in liver fibrosis Gastroenterology 135 5 2008 1729 1738 18823985
  20. [22]Sakata K. Eda S. Lee E.S. Hara M. Imoto M. Kojima S. Neovessel formation promotes liver fibrosis via providing latent transforming growth factor-β Biochem Biophys Res Commun 443 3 2014 950 956 24361885
  21. [23]Liu L. You Z. Yu H. Zhou L. Zhao H. Yan X. Mechanotransduction-modulated fibrotic microniches reveal the contribution of angiogenesis in liver fibrosis Nat Mater 16 12 2017 1252 1261 29170554
  22. [24]Glinka Y. Prud'homme G.J. Neuropilin-1 is a receptor for transforming growth factor beta-1, activates its latent form, and promotes regulatory T cell activity J Leukoc Biol 84 1 2008 302 310 18436584 PMC2504713
  23. [25]Ballmer-Hofer K. Andersson A.E. Ratcliffe L.E. Berger P. Neuropilin-1 promotes VEGFR-2 trafficking through Rab11 vesicles thereby specifying signal output Blood 118 3 2011 816 826 21586748
  24. [26]Shintani Y. Takashima S. Asano Y. Kato H. Liao Y. Yamazaki S. Glycosaminoglycan modification of neuropilin-1 modulates VEGFR2 signaling EMBO J 25 13 2006 3045 3055 16763549 PMC1500974
  25. [27]Hamerlik P. Lathia J.D. Rasmussen R. Wu Q. Bartkova J. Lee M. Autocrine VEGF-VEGFR2-Neuropilin-1 signaling promotes glioma stem-like cell viability and tumor growth J Exp Med 209 3 2012 507 520 22393126 PMC3302235
  26. [28]Ren B. Deng Y. Mukhopadhyay A. Lanahan A.A. Zhuang Z.W. Moodie K.L. ERK1/2-Akt1 crosstalk regulates arteriogenesis in mice and zebrafish J Clin Invest 120 4 2010 1217 1228 20237411 PMC2846043
  27. [29]Gerber H.P. McMurtrey A. Kowalski J. Yan M. Keyt B.A. Dixit V. Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3′-kinase/Akt signal transduction pathway. Requirement for Flk-1/KDR activation J Biol Chem 273 46 1998 30336 30343 9804796
  28. [30]Kalluri R. Zeisberg M. Fibroblasts in cancer Nat Rev Cancer 6 5 2006 392 401 16572188

Cited by

Sorted by citations

Authors
Wang, L., Feng, Y., Xie, X., Wu, H., Su, X. N., Qi, J., Xin, W., Gao, L., Zhang, Y., Shah, V. H., & Zhu, Q.
Affiliations
  • Shandong University (CN)
  • Johns Hopkins University (US)
  • Mayo Clinic (US)
Corresponding author
Zhu, Qiang
ORCID
Venue
EBioMedicine
Publisher
Elsevier BV
Published
2019-05
Volume
43
Pages
525-536
ISSN
2352-3964 (ISSN-L)
DOI
10.1016/j.ebiom.2019.04.050
PMC
PMC6558257
OpenAlex
W2943081452
Cited by
66
References
2
Citations by year
2026: 7 · 2025: 14 · 2024: 9 · 2023: 10 · 2022: 9 · 2021: 11 · 2020: 5
FWCI
3.99
Type
journal article
Language
en
Open access
Licence
Locations
  • EBioMedicine (publishedVersion, cc-by-nc-nd)
  • SSRN Electronic Journal (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Natural Science Foundation of China
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
  • Health Sciences › Medicine › Hepatology › Liver Disease and Transplantation
Keywords
neuropilin-1, liver cirrhosis, angiogenesis, hepatic sinusoidal endothelial cells, VEGFR2, PI3K/Akt signaling, focal adhesion kinase, endothelial cell migration, endothelial tube formation, liver fibrosis, therapeutic target, hepatic stellate cells, vascular endothelial growth factor
MeSH terms
Animals, Cell Line, Humans, Liver Cirrhosis, Models, Biological, Neovascularization, Pathologic, Signal Transduction, Gene Expression, Phosphatidylinositol 3-Kinases, Neuropilin-1, Vascular Endothelial Growth Factor Receptor-2, Endothelial Cells, Tissue Culture Techniques, Proto-Oncogene Proteins c-akt, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review