Skip to main content
Log in

The effect of aging on VEGF/VEGFR2 signal pathway genes expression in rat liver sinusoidal endothelial cell

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Liver sinusoidal endothelial cells (LSECs) play a key role in the initiation and neoangiogenesis of liver regeneration. We presume that the abnormity of the VEGF/VEGFR2 and its pathway gene Id1, Wnt2 and HGF expression in aged LSECs may be an important mechanism to affect liver regeneration of the elderly. LSECs from two different groups (adult and old) were isolated in a rodent model, and observed by SEM and TEM. The adult and old rats were underwent 70% partial hepatectomy. The proliferation of hepatocytes and LSECs were analyzed by Immunofluorescence staining. The expression of VEGF/VEGFR2 and its pathway gene in isolated LSECs and liver tissue after hepatectomy were detected by qRT-PCR and Western blot. There is a decreased number of endothelial fenestrae in the LSECs of the old group, compared to the adult group. The old group had a lower expression of VEGF/VEGFR2 and its pathway gene than the adult groups (p < 0.01). The results of western blot were consistent with those of qRT-PCR. The hepatocytes had a high proliferation rate at first 4 days after hepatectomy, and a significantly higher proliferation rate in the adult group. The LSECs began to proliferate after 4 days of hepatectomy, and showed a quantity advantage in the adult group. The adult group had a significantly higher expression of VEGF/VEGFR2 and its pathway gene after hepatectomy than the old group (p < 0.01). LSCEs turn to be defenestration in structure and have a low expression of VEGF/VEGFR2 and its pathway gene with aging.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig.4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Clavien PA, Oberkofler CE, Raptis DA, Lehmann K, Rickenbacher A, El-Badry AM (2010) What is critical for liver surgery and partial liver transplantation: size or quality? Hepatology (Baltimore, MD) 52(2):715–729. https://doi.org/10.1002/hep.23713

    Article  Google Scholar 

  2. Michalopoulos GK, DeFrances MC (1997) Liver regeneration. Science (New York, NY) 276(5309):60–66

    Article  CAS  Google Scholar 

  3. Mackey S, Singh P, Darlington GJ (2003) Making the liver young again. Hepatology (Baltimore, MD) 38(6):1349–1352. https://doi.org/10.1016/j.hep.2003.10.007

    Article  CAS  Google Scholar 

  4. Schmucker DL (2005) Age-related changes in liver structure and function: implications for disease ? Exp Gerontol 40(8–9):650–659. https://doi.org/10.1016/j.exger.2005.06.009

    Article  CAS  PubMed  Google Scholar 

  5. Fausto N, Campbell JS, Riehle KJ (2006) Liver regeneration. Hepatology (Baltimore, MD) 43(2 Suppl 1):S45–53. https://doi.org/10.1002/hep.20969

    Article  CAS  Google Scholar 

  6. Ijtsma AJ, Boeve LM, van der Hilst CS, de Boer MT, de Jong KP, Peeters PM, Gouw AS, Porte RJ, Slooff MJ (2008) The survival paradox of elderly patients after major liver resections. J Gastrointest Surg 12(12):2196–2203. https://doi.org/10.1007/s11605-008-0563-2

    Article  PubMed  Google Scholar 

  7. Furrer K, Rickenbacher A, Tian Y, Jochum W, Bittermann AG, Kach A, Humar B, Graf R, Moritz W, Clavien PA (2011) Serotonin reverts age-related capillarization and failure of regeneration in the liver through a VEGF-dependent pathway. Proc Natl Acad Sci USA 108(7):2945–2950. https://doi.org/10.1073/pnas.1012531108

    Article  PubMed  Google Scholar 

  8. Clavien PA, Petrowsky H, DeOliveira ML, Graf R (2007) Strategies for safer liver surgery and partial liver transplantation. N Engl J Med 356(15):1545–1559. https://doi.org/10.1056/NEJMra065156

    Article  PubMed  Google Scholar 

  9. Wisse E, De Zanger RB, Charels K, Van Der Smissen P, McCuskey RS (1985) The liver sieve: considerations concerning the structure and function of endothelial fenestrae, the sinusoidal wall and the space of Disse. Hepatology (Baltimore, MD) 5(4):683–692

    Article  CAS  Google Scholar 

  10. Karrar A, Broome U, Uzunel M, Qureshi AR, Sumitran-Holgersson S (2007) Human liver sinusoidal endothelial cells induce apoptosis in activated T cells: a role in tolerance induction. Gut 56(2):243–252. https://doi.org/10.1136/gut.2006.093906

    Article  CAS  PubMed  Google Scholar 

  11. Warren A, Bertolino P, Benseler V, Fraser R, McCaughan GW, Le Couteur DG (2007) Marked changes of the hepatic sinusoid in a transgenic mouse model of acute immune-mediated hepatitis. J Hepatol 46(2):239–246. https://doi.org/10.1016/j.jhep.2006.08.022

    Article  CAS  PubMed  Google Scholar 

  12. DeLeve LD (2013) Liver sinusoidal endothelial cells and liver regeneration. J Clin Investig 123(5):1861–1866. https://doi.org/10.1172/jci66025

    Article  CAS  PubMed  Google Scholar 

  13. Carpenter B, Lin Y, Stoll S, Raffai RL, McCuskey R, Wang R (2005) VEGF is crucial for the hepatic vascular development required for lipoprotein uptake. Development (Cambridge, England) 132(14):3293–3303. https://doi.org/10.1242/dev.01902

    Article  CAS  Google Scholar 

  14. Ding BS, Nolan DJ, Butler JM, James D, Babazadeh AO, Rosenwaks Z, Mittal V, Kobayashi H, Shido K, Lyden D, Sato TN, Rabbany SY, Rafii S (2010) Inductive angiocrine signals from sinusoidal endothelium are required for liver regeneration. Nature 468(7321):310–315. https://doi.org/10.1038/nature09493

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Schmucker DL, Sanchez H (2011) Liver regeneration and aging: a current perspective. Curr Gerontol Geriatr Res 2011:526379. https://doi.org/10.1155/2011/526379

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Kan Z, Madoff DC (2008) Liver anatomy: microcirculation of the liver. Semin Intervent Rad 25(2):77–85. https://doi.org/10.1055/s-2008-1076685

    Article  Google Scholar 

  17. Ito Y, Sorensen KK, Bethea NW, Svistounov D, McCuskey MK, Smedsrod BH, McCuskey RS (2007) Age-related changes in the hepatic microcirculation in mice. Exp Gerontol 42(8):789–797. https://doi.org/10.1016/j.exger.2007.04.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Cheluvappa R, Hilmer SN, Kwun SY, Jamieson HA, O'Reilly JN, Muller M, Cogger VC, Le Couteur DG (2007) The effect of old age on liver oxygenation and the hepatic expression of VEGF and VEGFR2. Exp Gerontol 42(10):1012–1019. https://doi.org/10.1016/j.exger.2007.06.001

    Article  CAS  PubMed  Google Scholar 

  19. Smedsrod B, Pertoft H, Eggertsen G, Sundstrom C (1985) Functional and morphological characterization of cultures of Kupffer cells and liver endothelial cells prepared by means of density separation in Percoll, and selective substrate adherence. Cell Tissue Res 241(3):639–649

    Article  CAS  Google Scholar 

  20. Washburn WK, Johnson LB, Lewis WD, Jenkins RL (1996) Graft function and outcome of older (> or = 60 years) donor livers. Transplantation 61(7):1062–1066

    Article  CAS  Google Scholar 

  21. Yokomori H, Oda M, Yoshimura K, Nagai T, Fujimaki K, Watanabe S, Hibi T (2009) Caveolin-1 and Rac regulate endothelial capillary-like tubular formation and fenestral contraction in sinusoidal endothelial cells. Liver Int 29(2):266–276. https://doi.org/10.1111/j.1478-3231.2008.01891.x

    Article  CAS  PubMed  Google Scholar 

  22. DeLeve LD, Wang X, Hu L, McCuskey MK, McCuskey RS (2004) Rat liver sinusoidal endothelial cell phenotype is maintained by paracrine and autocrine regulation. Am J Physiol Gastrointest Liver Physiol 287(4):G757–763. https://doi.org/10.1152/ajpgi.00017.2004

    Article  CAS  PubMed  Google Scholar 

  23. Ohi N, Nishikawa Y, Tokairin T, Yamamoto Y, Doi Y, Omori Y, Enomoto K (2006) Maintenance of Bad phosphorylation prevents apoptosis of rat hepatic sinusoidal endothelial cells in vitro and in vivo. Am J Pathol 168(4):1097–1106. https://doi.org/10.2353/ajpath.2006.050462

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Harb R, Xie G, Lutzko C, Guo Y, Wang X, Hill CK, Kanel GC, DeLeve LD (2009) Bone marrow progenitor cells repair rat hepatic sinusoidal endothelial cells after liver injury. Gastroenterology 137(2):704–712. https://doi.org/10.1053/j.gastro.2009.05.009

    Article  PubMed  PubMed Central  Google Scholar 

  25. McCloskey TW, Todaro JA, Laskin DL (1992) Lipopolysaccharide treatment of rats alters antigen expression and oxidative metabolism in hepatic macrophages and endothelial cells. Hepatology (Baltimore, MD) 16(1):191–203

    Article  CAS  Google Scholar 

  26. Xie G, Wang L, Wang X, Wang L, DeLeve LD (2010) Isolation of periportal, midlobular, and centrilobular rat liver sinusoidal endothelial cells enables study of zonated drug toxicity. Am J Physiol Gastrointest Liver Physiol 299(5):G1204–1210. https://doi.org/10.1152/ajpgi.00302.2010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. March S, Hui EE, Underhill GH, Khetani S, Bhatia SN (2009) Microenvironmental regulation of the sinusoidal endothelial cell phenotype in vitro. Hepatology (Baltimore, MD) 50(3):920–928. https://doi.org/10.1002/hep.23085

    Article  CAS  Google Scholar 

  28. Elvevold K, Smedsrod B, Martinez I (2008) The liver sinusoidal endothelial cell: a cell type of controversial and confusing identity. Am J Physiol Gastrointest Liver Physiol 294(2):G391–400. https://doi.org/10.1152/ajpgi.00167.2007

    Article  CAS  PubMed  Google Scholar 

  29. Aravinthan A, Verma S, Coleman N, Davies S, Allison M, Alexander G (2012) Vacuolation in hepatocyte nuclei is a marker of senescence. J Clin Pathol 65(6):557–560. https://doi.org/10.1136/jclinpath-2011-200641

    Article  PubMed  Google Scholar 

  30. Raquel M-D, Martí O-R, Anabel F-I, Diana H, Leticia Mo JHA, Sergi V, Rubén F, Constantino F, Agustín A (2018) Effects of aging on liver microcirculatory function and sinusoidal phenotype. Aging Cell 17(6):e12829

    Article  Google Scholar 

  31. McLean AJ, Cogger VC, Chong GC, Warren A, Markus AM, Dahlstrom JE, Le Couteur DG (2003) Age-related pseudocapillarization of the human liver. J Pathol 200(1):112–117. https://doi.org/10.1002/path.1328

    Article  PubMed  Google Scholar 

  32. Hu J, Srivastava K, Wieland M, Runge A, Mogler C, Besemfelder E, Terhardt D, Vogel MJ, Cao L, Korn C, Bartels S, Thomas M, Augustin HG (2014) Endothelial cell-derived angiopoietin-2 controls liver regeneration as a spatiotemporal rheostat. Science (New York, NY) 343(6169):416–419. https://doi.org/10.1126/science.1244880

    Article  CAS  Google Scholar 

Download references

Acknowledegements

This study was supported by a grant from National Natural Science Foundation of China (No. 81270521 and 81870445). This work was also supported in part by the Youth Creative Project of Medical Research in Sichuan Province (Grant No. Q15087).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Bo Wang.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, WL., Zheng, XL., Li, QS. et al. The effect of aging on VEGF/VEGFR2 signal pathway genes expression in rat liver sinusoidal endothelial cell. Mol Cell Biochem 476, 269–277 (2021). https://doi.org/10.1007/s11010-020-03903-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-020-03903-7

Keywords

Navigation