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.
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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
Michalopoulos GK, DeFrances MC (1997) Liver regeneration. Science (New York, NY) 276(5309):60–66
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
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
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
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
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
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
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
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
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
DeLeve LD (2013) Liver sinusoidal endothelial cells and liver regeneration. J Clin Investig 123(5):1861–1866. https://doi.org/10.1172/jci66025
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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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).
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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
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DOI: https://doi.org/10.1007/s11010-020-03903-7