Relevance of VEGFA in rat livers subjected to partial hepatectomy under ischemia-reperfusion.
Animals
Hepatectomy
/ methods
Ischemia
/ metabolism
Liver
/ metabolism
Male
Phosphatidylinositol 3-Kinases
/ metabolism
Proto-Oncogene Proteins c-akt
/ metabolism
Rats
Rats, Sprague-Dawley
Rats, Zucker
Reperfusion Injury
/ metabolism
Signal Transduction
/ physiology
Survival Rate
Up-Regulation
/ physiology
Vascular Endothelial Growth Factor A
/ metabolism
Vascular Endothelial Growth Factor Receptor-1
/ metabolism
Wnt2 Protein
/ metabolism
Adipose tissue
Ischemia-reperfusion
Liver
Soluble vascular endothelial growth factor receptor 1
Steatosis
Vascular endothelial growth factor A
Journal
Journal of molecular medicine (Berlin, Germany)
ISSN: 1432-1440
Titre abrégé: J Mol Med (Berl)
Pays: Germany
ID NLM: 9504370
Informations de publication
Date de publication:
09 2019
09 2019
Historique:
received:
14
11
2018
accepted:
06
06
2019
revised:
13
05
2019
pubmed:
30
6
2019
medline:
18
6
2020
entrez:
30
6
2019
Statut:
ppublish
Résumé
We examined the effects of VEGFA on damage and regeneration in steatotic and non-steatotic livers of rats submitted to PH under I/R, and characterized the underlying mechanisms involved. Our results indicated that VEGFA levels were decreased in both steatotic and non-steatotic livers after surgery. The administration of VEGFA increased VEGFA levels in non-steatotic livers, reducing the incidence of post-operative complications following surgery through the VEGFR2-Wnt2 pathway, independently of Id1. Unexpectedly, administration of VEGFA notably reduced VEGFA levels in steatotic livers, exacerbating damage and regenerative failure. After exogenous administration of VEGFA in steatotic animals, circulating VEGFA is sequestered by the high circulating levels of sFlt1 released from adipose tissue. Under such conditions, VEGFA cannot reach the steatotic liver to exert its effects. Consequently, the concomitant administration of VEGFA and an antibody against sFlt1 was required to avoid binding of sFlt1 to VEGFA. This was associated with high VEGFA levels in steatotic livers and protection against damage and regenerative failure, plus improvement in the survival rate via up-regulation of PI3K/Akt independently of the Id1-Wnt2 pathway. The current study highlights the different effects and signaling pathways of VEGFA in liver surgery requiring PH and I/R based in the presence of steatosis. KEY MESSAGES: VEGFA administration improves PH+I/R injury only in non-steatotic livers of Ln animals. VEGFA benefits are exerted through the VEGFR2-Wnt2 pathway in non-steatotic livers. In Ob rats, exogenous VEGFA is sequestered by circulating sFlt1, exacerbating liver damage. Therapeutic combination of VEGFA and anti-sFlt1 is required to protect steatotic livers. VEGFA+anti-sFlt1 treatment protects steatotic livers through a VEGFR2-PI3K/Akt pathway.
Identifiants
pubmed: 31254006
doi: 10.1007/s00109-019-01811-y
pii: 10.1007/s00109-019-01811-y
pmc: PMC6713699
doi:
Substances chimiques
Vascular Endothelial Growth Factor A
0
Wnt2 Protein
0
vascular endothelial growth factor A, rat
0
Vascular Endothelial Growth Factor Receptor-1
EC 2.7.10.1
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1299-1314Références
Oncogene. 1999 Apr 1;18(13):2221-30
pubmed: 10327068
Biochem Biophys Res Commun. 1999 Jul 22;261(1):118-22
pubmed: 10405333
Hepatology. 2001 Apr;33(4):808-15
pubmed: 11283843
J Anat. 2002 Jun;200(6):581-97
pubmed: 12162726
Cancer Res. 2002 Aug 15;62(16):4645-55
pubmed: 12183421
J Clin Invest. 2003 Dec;112(12):1785-8
pubmed: 14679172
J Biol Chem. 2004 May 21;279(21):22267-75
pubmed: 15026417
Hepatology. 2004 Dec;40(6):1252-5
pubmed: 15558710
J Clin Invest. 2005 May;115(5):1111-9
pubmed: 15864338
Transplantation. 2005 May 15;79(9):1110-5
pubmed: 15880052
EMBO J. 2005 Jul 6;24(13):2342-53
pubmed: 15962004
Rev Esp Enferm Dig. 2005 Oct;97(10):699-706
pubmed: 16351462
Am J Pathol. 2006 Feb;168(2):695-705
pubmed: 16436682
J Hepatol. 2006 Oct;45(4):494-9
pubmed: 16919359
Gastroenterology. 2006 Sep;131(3):934-45
pubmed: 16952562
Ann Surg. 2007 Jan;245(1):20-30
pubmed: 17197961
J Clin Invest. 2007 Jan;117(1):89-93
pubmed: 17200712
J Surg Res. 2007 Apr;138(2):291-9
pubmed: 17275844
Cancer Gene Ther. 2007 May;14(5):488-98
pubmed: 17363959
Diabetes. 2007 Apr;56(4):901-11
pubmed: 17395738
Ann Surg. 2007 Jun;245(6):923-30
pubmed: 17522518
Cell Signal. 2007 Oct;19(10):2003-12
pubmed: 17658244
J Cardiothorac Surg. 2007 Sep 21;2:38
pubmed: 17888151
J Gastroenterol Hepatol. 2007 Dec;22(12):2053-4
pubmed: 18031360
Cytokine. 2008 Oct;44(1):14-7
pubmed: 18656381
Mol Cell Biol. 2009 Mar;29(6):1575-91
pubmed: 19114551
J Pharmacol Exp Ther. 2009 Apr;329(1):130-40
pubmed: 19116369
J Am Soc Nephrol. 2009 Oct;20(10):2235-45
pubmed: 19608702
Proc Natl Acad Sci U S A. 2009 Jul 21;106(29):11960-5
pubmed: 19617534
Annu Rev Pathol. 2011;6:275-97
pubmed: 21034223
Nature. 2010 Nov 11;468(7321):310-5
pubmed: 21068842
Arch Med Res. 2011 Jan;42(1):38-43
pubmed: 21376261
Liver Transpl. 2011 Sep;17(9):993-1004
pubmed: 21671349
Cytokine. 2012 Aug;59(2):442-9
pubmed: 22658783
Transl Psychiatry. 2011 Nov 22;1:e56
pubmed: 22833211
Shock. 2013 Jan;39(1):3-10
pubmed: 23143067
Obesity (Silver Spring). 2014 Jan;22(1):151-8
pubmed: 23512909
Development. 2013 Aug;140(15):3079-93
pubmed: 23861057
Dig Dis Sci. 2014 Feb;59(2):365-74
pubmed: 24048683
Liver Int. 2014 Aug;34(7):e271-89
pubmed: 24107124
Digestion. 2013;88(4):235-42
pubmed: 24281241
Am J Transplant. 2016 Apr;16(4):1148-59
pubmed: 26704922
PLoS One. 2016 Mar 01;11(3):e0150446
pubmed: 26930285
J Cell Mol Med. 2017 Oct;21(10):2344-2358
pubmed: 28374452
Signal Transduct Target Ther. 2017;2:null
pubmed: 29201496
Ann Surg. 2018 Nov;268(5):885-893
pubmed: 30080721
Biochem Biophys Res Commun. 1996 Sep 13;226(2):324-8
pubmed: 8806634
J Biol Chem. 1998 Nov 13;273(46):30336-43
pubmed: 9804796