Blockade of vascular endothelial growth factor receptor 2 inhibits intraplaque haemorrhage by normalization of plaque neovessels

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 pla...

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Published inJournal of internal medicine Vol. 285; no. 1; pp. 59 - 74
Main Authors de Vries, M. R., Parma, L., Peters, H. A. B., Schepers, A., Hamming, J. F., Jukema, J. W., Goumans, M. J. T. H., Guo, L., Finn, A. V., Virmani, R., Ozaki, C. K., Quax, P. H. A.
Format Journal Article
LanguageEnglish
Published England Blackwell Publishing Ltd 01.01.2019
John Wiley and Sons Inc
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Abstract 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.
AbstractList BackgroundPlaque 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.ObjectiveBlockade 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 ResultsIn 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.ConclusionInhibition of intraplaque haemorrhage by controlling neovessels maturation holds promise to improve plaque stability.
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.
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.
Author Finn, A. V.
Peters, H. A. B.
Virmani, R.
Guo, L.
Quax, P. H. A.
Hamming, J. F.
de Vries, M. R.
Ozaki, C. K.
Parma, L.
Jukema, J. W.
Schepers, A.
Goumans, M. J. T. H.
AuthorAffiliation 3 Department of Cardiology Leiden University Medical Center Leiden The Netherlands
5 CVPath Institute Inc. Gaithersburg MD USA
1 Department of Surgery Leiden University Medical Center Leiden The Netherlands
2 Einthoven Laboratory for Experimental Vascular Medicine Leiden University Medical Center Leiden The Netherlands
4 Department of Cell and Chemical Biology Leiden University Medical Center Leiden The Netherlands
6 Department of Surgery Division of Vascular and Endovascular Surgery Brigham and Women's Hospital Harvard Medical School Boston MA USA
AuthorAffiliation_xml – name: 3 Department of Cardiology Leiden University Medical Center Leiden The Netherlands
– name: 2 Einthoven Laboratory for Experimental Vascular Medicine Leiden University Medical Center Leiden The Netherlands
– name: 6 Department of Surgery Division of Vascular and Endovascular Surgery Brigham and Women's Hospital Harvard Medical School Boston MA USA
– name: 4 Department of Cell and Chemical Biology Leiden University Medical Center Leiden The Netherlands
– name: 1 Department of Surgery Leiden University Medical Center Leiden The Netherlands
– name: 5 CVPath Institute Inc. Gaithersburg MD USA
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ContentType Journal Article
Copyright 2018 The Authors. published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.
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.
Copyright © 2019 The Association for the Publication of the Journal of Internal Medicine
Copyright_xml – notice: 2018 The Authors. published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.
– notice: 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.
– notice: Copyright © 2019 The Association for the Publication of the Journal of Internal Medicine
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Issue 1
Keywords atherosclerosis
intraplaque haemorrhage
angiogenesis
vascular endothelial growth factor
vein graft
Language English
License Attribution
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.
This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
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Snippet Background Plaque angiogenesis is associated with atherosclerotic lesion growth, plaque instability and negative clinical outcome. Plaque angiogenesis is a...
Plaque angiogenesis is associated with atherosclerotic lesion growth, plaque instability and negative clinical outcome. Plaque angiogenesis is a natural...
BackgroundPlaque angiogenesis is associated with atherosclerotic lesion growth, plaque instability and negative clinical outcome. Plaque angiogenesis is a...
BACKGROUNDPlaque angiogenesis is associated with atherosclerotic lesion growth, plaque instability and negative clinical outcome. Plaque angiogenesis is a...
SourceID pubmedcentral
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pubmed
wiley
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Index Database
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StartPage 59
SubjectTerms Angiogenesis
Angiopoietin
Angiopoietin-2 - blood
Animals
Aorta
Arteriosclerosis
Atherosclerosis
Biomarkers - blood
Blood vessels
Carotid artery
Collagen
Connexins - blood
Control stability
Disease Models, Animal
Erythrocytes
Gap Junction alpha-5 Protein
Grafting
Grafts
Growth factors
Hemorrhage
Hemorrhage - prevention & control
Humans
Hypoxia
Inflammation
intraplaque haemorrhage
Lesions
Macrophages
Maturation
Mice
Muscles
Neovascularization, Pathologic - prevention & control
Original
Plaque, Atherosclerotic - drug therapy
SDF-1 protein
Smooth muscle
Stability
Vascular endothelial growth factor
Vascular Endothelial Growth Factor A - blood
Vascular Endothelial Growth Factor A - pharmacology
Vascular endothelial growth factor receptor 2
Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors
vein graft
Veins & arteries
Title Blockade of vascular endothelial growth factor receptor 2 inhibits intraplaque haemorrhage by normalization of plaque neovessels
URI https://onlinelibrary.wiley.com/doi/abs/10.1111%2Fjoim.12821
https://www.ncbi.nlm.nih.gov/pubmed/30102798
https://www.proquest.com/docview/2158402962
https://search.proquest.com/docview/2088290547
https://pubmed.ncbi.nlm.nih.gov/PMC6334526
Volume 285
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