Blockade of vascular endothelial growth factor receptor 2 inhibits intraplaque haemorrhage by normalization of plaque neovessels.
Angiopoietin-2
/ blood
Animals
Biomarkers
/ blood
Connexins
/ blood
Disease Models, Animal
Hemorrhage
/ prevention & control
Humans
Mice
Neovascularization, Pathologic
/ prevention & control
Plaque, Atherosclerotic
/ drug therapy
Vascular Endothelial Growth Factor A
/ blood
Vascular Endothelial Growth Factor Receptor-2
/ antagonists & inhibitors
Gap Junction alpha-5 Protein
angiogenesis
atherosclerosis
intraplaque haemorrhage
vascular endothelial growth factor
vein graft
Journal
Journal of internal medicine
ISSN: 1365-2796
Titre abrégé: J Intern Med
Pays: England
ID NLM: 8904841
Informations de publication
Date de publication:
01 2019
01 2019
Historique:
pubmed:
14
8
2018
medline:
22
11
2019
entrez:
14
8
2018
Statut:
ppublish
Résumé
Plaque angiogenesis is associated with atherosclerotic lesion growth, plaque instability and negative clinical outcome. Plaque angiogenesis is a natural occurring process to fulfil the increasing demand of oxygen and nourishment of the vessel wall. However, inadequate formed, immature plaque neovessels are leaky and cause intraplaque haemorrhage. Blockade of VEGFR2 normalizes the unbridled process of plaque neovessel formation and induces maturation of nascent vessels resulting in prevention of intraplaque haemorrhage and influx of inflammatory cells into the plaque and subsequently increases plaque stability. In human carotid and vein graft atherosclerotic lesions, leaky plaque neovessels and intraplaque haemorrhage co-localize with VEGF/VEGFR2 and angiopoietins. Using hypercholesterolaemic ApoE3*Leiden mice that received a donor caval vein interposition in the carotid artery, we demonstrate that atherosclerotic vein graft lesions at t28 are associated with hypoxia, Hif1α and Sdf1 up-regulation. Local VEGF administration results in increased plaque angiogenesis. VEGFR2 blockade in this model results in a significant 44% decrease in intraplaque haemorrhage and 80% less extravasated erythrocytes compared to controls. VEGFR2 blockade in vivo results in a 32% of reduction in vein graft size and more stable lesions with significantly reduced macrophage content (30%), and increased collagen (54%) and smooth muscle cell content (123%). Significant decreased VEGF, angiopoietin-2 and increased Connexin 40 expression levels demonstrate increased plaque neovessel maturation in the vein grafts. VEGFR2 blockade in an aortic ring assay showed increased pericyte coverage of the capillary sprouts. Inhibition of intraplaque haemorrhage by controlling neovessels maturation holds promise to improve plaque stability.
Sections du résumé
BACKGROUND
Plaque angiogenesis is associated with atherosclerotic lesion growth, plaque instability and negative clinical outcome. Plaque angiogenesis is a natural occurring process to fulfil the increasing demand of oxygen and nourishment of the vessel wall. However, inadequate formed, immature plaque neovessels are leaky and cause intraplaque haemorrhage.
OBJECTIVE
Blockade of VEGFR2 normalizes the unbridled process of plaque neovessel formation and induces maturation of nascent vessels resulting in prevention of intraplaque haemorrhage and influx of inflammatory cells into the plaque and subsequently increases plaque stability.
METHODS AND RESULTS
In human carotid and vein graft atherosclerotic lesions, leaky plaque neovessels and intraplaque haemorrhage co-localize with VEGF/VEGFR2 and angiopoietins. Using hypercholesterolaemic ApoE3*Leiden mice that received a donor caval vein interposition in the carotid artery, we demonstrate that atherosclerotic vein graft lesions at t28 are associated with hypoxia, Hif1α and Sdf1 up-regulation. Local VEGF administration results in increased plaque angiogenesis. VEGFR2 blockade in this model results in a significant 44% decrease in intraplaque haemorrhage and 80% less extravasated erythrocytes compared to controls. VEGFR2 blockade in vivo results in a 32% of reduction in vein graft size and more stable lesions with significantly reduced macrophage content (30%), and increased collagen (54%) and smooth muscle cell content (123%). Significant decreased VEGF, angiopoietin-2 and increased Connexin 40 expression levels demonstrate increased plaque neovessel maturation in the vein grafts. VEGFR2 blockade in an aortic ring assay showed increased pericyte coverage of the capillary sprouts.
CONCLUSION
Inhibition of intraplaque haemorrhage by controlling neovessels maturation holds promise to improve plaque stability.
Identifiants
pubmed: 30102798
doi: 10.1111/joim.12821
pmc: PMC6334526
doi:
Substances chimiques
Angiopoietin-2
0
Biomarkers
0
Connexins
0
Vascular Endothelial Growth Factor A
0
Vascular Endothelial Growth Factor Receptor-2
EC 2.7.10.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
59-74Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL133500
Pays : United States
Informations de copyright
© 2018 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.
Références
Cancer Cell. 2004 Dec;6(6):553-63
pubmed: 15607960
Circulation. 1995 Jun 1;91(11):2793-801
pubmed: 7758186
Cancer Cell. 2014 Nov 10;26(5):605-22
pubmed: 25517747
J Am Coll Cardiol. 2009 Apr 28;53(17):1517-27
pubmed: 19389562
Atherosclerosis. 2011 Oct;218(2):369-77
pubmed: 21868015
Front Cardiovasc Med. 2018 Jan 24;5:3
pubmed: 29417051
Nat Rev Cardiol. 2016 Feb;13(2):79-98
pubmed: 26503410
Pharmacol Ther. 2016 Aug;164:204-25
pubmed: 27288725
Circulation. 1999 Apr 6;99(13):1726-32
pubmed: 10190883
Nat Med. 2003 Jun;9(6):685-93
pubmed: 12778167
Eur J Pharmacol. 2017 Dec 5;816:107-115
pubmed: 28435093
Proc Natl Acad Sci U S A. 2017 Apr 11;114(15):E3022-E3031
pubmed: 28348206
Arterioscler Thromb Vasc Biol. 2005 Oct;25(10):2054-61
pubmed: 16037567
J Biol Chem. 2001 Mar 9;276(10):7614-20
pubmed: 11108718
Blood. 2007 Jan 1;109(1):122-9
pubmed: 16990600
Proc Natl Acad Sci U S A. 2012 Oct 23;109(43):17561-6
pubmed: 23045683
J Vasc Surg. 1998 Jan;27(1):167-73
pubmed: 9474095
Vascul Pharmacol. 2018 Jan;100:34-40
pubmed: 29079346
J Am Coll Cardiol. 2008 Apr 1;51(13):1258-65
pubmed: 18371555
Curr Opin Lipidol. 2016 Oct;27(5):499-506
pubmed: 27472406
J Vasc Res. 2008;45(3):244-50
pubmed: 18182823
J Atheroscler Thromb. 2015;22(10):1100-12
pubmed: 26016418
J Vasc Surg. 2009 Jul;50(1):152-60
pubmed: 19563963
PLoS One. 2012;7(10):e47134
pubmed: 23071737
Circ Cardiovasc Imaging. 2014 Nov;7(6):920-9
pubmed: 25170063
Eur Heart J. 2011 Aug;32(16):1977-85, 1985a, 1985b, 1985c
pubmed: 21398643
Cardiovasc Res. 2010 Jul 15;87(2):262-71
pubmed: 20400620
J Intern Med. 2019 Jan;285(1):59-74
pubmed: 30102798
Nature. 2011 May 19;473(7347):298-307
pubmed: 21593862
J Vasc Surg. 1997 Jul;26(1):79-86
pubmed: 9240325
Arterioscler Thromb Vasc Biol. 2003 Mar 1;23(3):440-6
pubmed: 12615689
Angiogenesis. 2015 Apr;18(2):191-200
pubmed: 25537851
Nat Rev Cardiol. 2016 Aug;13(8):451-70
pubmed: 27194091
Arterioscler Thromb Vasc Biol. 2011 May;31(5):1033-40
pubmed: 21330606
J Surg Res. 2000 Jun 1;91(1):32-7
pubmed: 10816346
Sci Rep. 2016 Apr 07;6:24248
pubmed: 27053419
Arterioscler Thromb Vasc Biol. 2010 Jul;30(7):1282-92
pubmed: 20554950
Circ Res. 2002 Oct 4;91(7):577-84
pubmed: 12364385
Exp Dermatol. 2004 Nov;13(11):671-81
pubmed: 15500639
Ann Vasc Surg. 2014 Apr;28(3):725-36
pubmed: 24345704
Cancer Res. 2013 May 15;73(10):2943-8
pubmed: 23440426
Cancer Metastasis Rev. 1998 Jun;17(2):155-61
pubmed: 9770111
J Clin Invest. 2018 Mar 1;128(3):1106-1124
pubmed: 29457790