title: Angiopoietin-2 blocking antibodies reduce early atherosclerotic plaque development in mice.
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.
authors.affiliation: Department of Pathology, CARIM, Maastricht University Medical Center, P. Debyelaan 25, 6229 HX Maastricht, The Netherlands.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Theelen
authors.affiliation: Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Neulaniementie 2, 70150 Kuopio, Finland.
authors.forename: Jari P
authors.initials: JP
authors.lastname: Lappalainen
authors.affiliation: Department of Pathology, CARIM, Maastricht University Medical Center, P. Debyelaan 25, 6229 HX Maastricht, The Netherlands.
authors.forename: Judith C
authors.initials: JC
authors.lastname: Sluimer
authors.affiliation: Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Neulaniementie 2, 70150 Kuopio, Finland.
authors.forename: Erika
authors.initials: E
authors.lastname: Gurzeler
authors.affiliation: Department of Pathology, CARIM, Maastricht University Medical Center, P. Debyelaan 25, 6229 HX Maastricht, The Netherlands.
authors.forename: Jack P
authors.initials: JP
authors.lastname: Cleutjens
authors.affiliation: Department of Pathology, CARIM, Maastricht University Medical Center, P. Debyelaan 25, 6229 HX Maastricht, The Netherlands; Department of Molecular Genetics, CARIM, Maastricht University, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands; Department of Medical Biochemistry, Amsterdam Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Marion J
authors.initials: MJ
authors.lastname: Gijbels
authors.affiliation: Department of Pathology, CARIM, Maastricht University Medical Center, P. Debyelaan 25, 6229 HX Maastricht, The Netherlands.
authors.forename: Erik A L
authors.initials: EA
authors.lastname: Biessen
authors.affiliation: Department of Pathology, Amsterdam Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Mat J A P
authors.initials: MJ
authors.lastname: Daemen
authors.affiliation: Wihuri Research Institute and Translational Cancer Biology Program, University of Helsinki, Biomedicum Helsinki, Haartmaninkatu 8, 00290 Helsinki, Finland.
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
authors.affiliation: Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Neulaniementie 2, 70150 Kuopio, Finland. Electronic address: seppo.ylaherttuala@uef.fi.
authors.forename: Seppo
authors.initials: S
authors.lastname: Ylä-Herttuala
mesh_terms: D042702:Angiopoietin-2 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001018:Aortic Diseases / Q000097:blood / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D053299:Apolipoprotein B-100 / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000097:blood / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D016122:Brachiocephalic Trunk / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002339:Carotid Arteries / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002340:Carotid Artery Diseases / Q000097:blood / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D002791:Cholesterol, Dietary / Q000097:blood; D004195:Disease Models, Animal; D006937:Hypercholesterolemia / Q000097:blood / Q000150:complications / Q000235:genetics; D008297:Male; D018345:Mice, Knockout; D058226:Plaque, Atherosclerotic; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D013997:Time Factors; D014280:Triglycerides / Q000097:blood
chemical_list: D042702:Angiopoietin-2; D000906:Antibodies; D053299:Apolipoprotein B-100; D002791:Cholesterol, Dietary; D011973:Receptors, LDL; D014280:Triglycerides
keywords: Angiogenesis; Angiopoietin-2; Atherosclerosis; Microvascular leakage; Plaque stability