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Angiopoietin-2 blocking antibodies reduce early atherosclerotic plaque development in mice

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Author(s): Thomas L. Theelen ^a ^, ¹ , Jari P. Lappalainen ^b ^, ¹ , Judith C. Sluimer ^a ^, ¹ , Erika Gurzeler ^b , Jack P. Cleutjens ^a , Marion J. Gijbels ^a ^, ^c ^, ^d , Erik A.L. Biessen ^a , Mat J.A.P. Daemen ^e , Kari Alitalo ^f , Seppo Ylä-Herttuala ^b ^, ^∗

Publication date PMC-release: 1 August 2015

Journal: Atherosclerosis

Publisher: Elsevier

Keywords: Angiogenesis, Microvascular leakage, Plaque stability, Angiopoietin-2, Atherosclerosis, Ang-1, angiopoietin-1, Ang-2, angiopoietin-2, ApoB, apolipoprotein B, LDLr, low density lipoprotein receptor, MMP, matrix metalloproteinase, VEGF-A, vascular endothelial growth factor-A

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Abstract

Objective

Angiopoietin-2 (Ang-2) blocking agents are currently undergoing clinical trials for use in cancer treatment. Ang-2 has also been associated with rupture-prone atherosclerotic plaques in humans, suggesting a role for Ang-2 in plaque stability. Despite the availability of Ang-2 blocking agents, their clinical use is still lacking. Our aim was to establish if Ang-2 has a role in atheroma development and in the transition of subclinical to clinically relevant atherosclerosis. We investigated the effect of antibody-mediated Ang-2 blockage on atherogenesis after in a mouse model of atherosclerosis.

Methods

Hypercholesterolemic (low-density lipoprotein receptor ^−/− apolipoprotein B ^100/100) mice were subjected to high-cholesterol diet for eight weeks, one group with and one group without Ang-2 blocking antibody treatment during weeks 4–8.To enhance plaque development, a peri-adventitial collar was placed around the carotid arteries at the start of antibody treatment. Aortic root, carotid arteries and brachiocephalic arteries were analyzed to evaluate the effect of Ang-2 blockage on atherosclerotic plaque size and stable plaque characteristics.

Results

Anti-Ang-2 treatment reduced the size of fatty streaks in the brachiocephalic artery (−72%, p < 0.05). In addition, antibody-mediated Ang-2 blockage reduced plasma triglycerides (−27%, p < 0.05). In contrast, Ang-2 blockage did not have any effect on the size or composition (collagen content, macrophage percentage, adventitial microvessel density) of pre-existing plaques in the aortic root or collar-induced plaques in the carotid artery.

Conclusions

Ang-2 blockage was beneficial as it decreased fatty streak formation and plasma triglyceride levels, but had no adverse effect on pre-existing atherosclerosis in hypercholesterolemic mice.

Highlights

•

Antibody-mediated Ang-2 blockage delays fatty streak formation in mice.
•

Ang-2 blockage lowers plasma triglyceride levels.
•

Ang-2 blockage has no negative effects on preexisting atherosclerosis.

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Most cited references 41

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Angiopoietin-2 sensitizes endothelial cells to TNF-alpha and has a crucial role in the induction of inflammation.

Ulrike Fiedler, Yvonne Reiss, Marion Scharpfenecker … (2006)

The angiopoietins Ang-1 and Ang-2 have been identified as ligands of the receptor tyrosine kinase Tie-2 (refs. 1,2). Paracrine Ang-1-mediated activation of Tie-2 acts as a regulator of vessel maturation and vascular quiescence. In turn, the antagonistic ligand Ang-2 acts by an autocrine mechanism and is stored in endothelial Weibel-Palade bodies from where it can be rapidly released upon stimulation. The rapid release of Ang-2 implies functions of the angiopoietin-Tie system beyond its established role during vascular morphogenesis as a regulator of rapid vascular responses. Here we show that mice deficient in Ang-2 (encoded by the gene Angpt2) cannot elicit an inflammatory response in thioglycollate-induced or Staphylococcus aureus-induced peritonitis, or in the dorsal skinfold chamber model. Recombinant Ang-2 restores the inflammation defect in Angpt2(-/-) mice. Intravital microscopy showed normal TNF-alpha-induced leukocyte rolling in the vasculature of Angpt2(-/-)mice, but rolling cells did not firmly adhere to activated endothelium. Cellular experiments showed that Ang-2 promotes adhesion by sensitizing endothelial cells toward TNF-alpha and modulating TNF-alpha-induced expression of endothelial cell adhesion molecules. Together, these findings identify Ang-2 as an autocrine regulator of endothelial cell inflammatory responses. Ang-2 thereby acts as a switch of vascular responsiveness exerting a permissive role for the activities of proinflammatory cytokines.

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Arterial thromboembolic events in patients with metastatic carcinoma treated with chemotherapy and bevacizumab.

Wang Wang, Hans Gerber, Herbert Hurwitz … (2007)

Although combination treatment with bevacizumab (humanized monoclonal antibody against vascular endothelial growth factor) and chemotherapy improves survival of patients with various metastatic carcinomas, an increased risk of arterial thromboembolic events has been observed in some trials. We characterized this risk by performing post hoc analyses of randomized controlled trials that evaluated combination treatment with bevacizumab and chemotherapy versus chemotherapy alone. Low-dose aspirin was permitted in these trials, and its safety was also analyzed. Data were pooled from five randomized controlled trials that included a total of 1745 patients with metastatic colorectal, breast, or non-small-cell lung carcinoma. The risk of an arterial or venous thromboembolic event was assessed by simple incidence rates, rates per 100 person-years, and/or hazard ratios (HRs). The association between patient characteristics and risk of an arterial thromboembolic event was investigated primarily by Cox proportional hazards regression. The relationship between low-dose aspirin and bleeding was explored by incidence rates and rates per 100 person-years. Combined treatment with bevacizumab and chemotherapy, compared with chemotherapy alone, was associated with increased risk for an arterial thromboembolic event (HR = 2.0, 95% confidence interval [CI] = 1.05 to 3.75; P = .031) but not for a venous thromboembolic event (HR = 0.89, 95% CI = 0.66 to 1.20; P = .44). The absolute rate of developing an arterial thromboembolism was 5.5 events per 100 person-years for those receiving combination therapy and 3.1 events per 100 person-years for those receiving chemotherapy alone (ratio = 1.8, 95% CI = 0.94 to 3.33; P = .076). Development of an arterial thromboembolic event was associated with a prior arterial thromboembolic event (P<.001) or age of 65 years or older (P = .01). Baseline or on-study aspirin use was associated with modest increases in grade 3 and 4 bleeding events in both treatment groups, from 3.6% to 4.7% for bevacizumab-treated patients and from 1.7% to 2.2% for control subjects. Combination treatment with bevacizumab and chemotherapy, compared with chemotherapy alone, was associated with an increased risk of arterial thromboembolism but not venous thromboembolism.

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VEGF and angiopoietin signaling in tumor angiogenesis and metastasis.

Pipsa Saharinen, Lauri Eklund, Kristina Pulkki … (2011)

Solid tumors require blood vessels for growth and dissemination, and lymphatic vessels as additional conduits for metastatic spread. The identification of growth factor receptor pathways regulating angiogenesis has led to the clinical approval of the first antiangiogenic molecules targeted against the vascular endothelial growth factor (VEGF)-VEGF receptor (VEGFR)-2 pathway. However, in many cases resistance to anti-VEGF-VEGFR therapy occurs, and thus far the clinical benefit has been limited to only modest improvements in overall survival. Therefore, novel treatment modalities are required. Here, we discuss the members of the VEGF-VEGFR family as well as the angiopoietin growth factors and their Tie receptors as potential novel targets for antiangiogenic and antilymphangiogenic therapies. Copyright © 2011 Elsevier Ltd. All rights reserved.

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Author and article information

Contributors

Seppo Ylä-Herttuala

Journal

Journal ID (nlm-ta): Atherosclerosis

Journal ID (iso-abbrev): Atherosclerosis

Title: Atherosclerosis

Publisher: Elsevier

ISSN (Print): 0021-9150

ISSN (Electronic): 1879-1484

Publication date PMC-release: 1 August 2015

Publication date (Print): August 2015

Volume: 241

Issue: 2

Pages: 297-304

Affiliations

[a ]Department of Pathology, CARIM, Maastricht University Medical Center, P. Debyelaan 25, 6229 HX Maastricht, The Netherlands

[b ]Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Neulaniementie 2, 70150 Kuopio, Finland

[c ]Department of Molecular Genetics, CARIM, Maastricht University, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands

[d ]Department of Medical Biochemistry, Amsterdam Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands

[e ]Department of Pathology, Amsterdam Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands

[f ]Wihuri Research Institute and Translational Cancer Biology Program, University of Helsinki, Biomedicum Helsinki, Haartmaninkatu 8, 00290 Helsinki, Finland

Author notes

[∗ ]Corresponding author. University of Eastern Finland, A.I. Virtanen Institute for Molecular Sciences, Department of Biotechnology and Molecular Medicine, P.O. Box 1627, FI-70211 Kuopio, Finland. seppo.ylaherttuala@ 123456uef.fi

[1]

Authors contributed equally.

Article

Publisher ID: S0021-9150(15)01332-5

DOI: 10.1016/j.atherosclerosis.2015.05.018

PMC ID: 4549395

PubMed ID: 26062989

SO-VID: db9ecb93-66c5-4d66-934d-b222e0144f00

Copyright © © 2015 The Authors

License:

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

History

Date received : 19 February 2015

Date revision received : 4 May 2015

Date accepted : 20 May 2015

Categories

Subject: Article

ScienceOpen disciplines: Immunology

Keywords: angiogenesis,microvascular leakage,plaque stability,angiopoietin-2,atherosclerosis,ang-1, angiopoietin-1,ang-2, angiopoietin-2,apob, apolipoprotein b,ldlr, low density lipoprotein receptor,mmp, matrix metalloproteinase,vegf-a, vascular endothelial growth factor-a

Data availability:

ScienceOpen disciplines: Immunology

Keywords: angiogenesis, microvascular leakage, plaque stability, angiopoietin-2, atherosclerosis, ang-1, angiopoietin-1, ang-2, angiopoietin-2, apob, apolipoprotein b, ldlr, low density lipoprotein receptor, mmp, matrix metalloproteinase, vegf-a, vascular endothelial growth factor-a

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