title: Angiogenesis Inhibitor, Endostar, Prevents Vasa Vasorum Neovascularization in a Swine Atherosclerosis Model.
abstract: OBJECTIVE
  Vasa vasorum neovascularization is a key feature of atherosclerosis (AS) and is strongly associated with inflammatory infiltration, lipid deposition, intraplaque hemorrhage, and hemosiderin deposit. Here we investigate the effects of Endostar, a strong anti-angiogenic drug, on vasa vasorum neovascularization in the experimental porcine model of early AS.
  
  
  METHODS
  Eighteen adult male Ba-Ma mini pigs were randomized into three groups, with six animals in each group. The pigs in the normal (N) group were fed a normal diet for 18 weeks, without balloon injury surgery. The animals in the atherosclerotic (AS) control and AS＋Endostar groups were fed a hypercholesterolemic diet for 12 weeks after balloon injury surgery; they received either saline or Endostar for an additional six weeks, while continuing the hypercholesterolemic diet. The atherosclerotic abdominal aorta and levels of serum lipids, TNF-alpha, IL-6, and hs-CRP were analyzed at 18 weeks.
  
  
  RESULTS
  The AS group had a significantly higher body weight and serum lipid concentration levels than the N group (p ＜ 0.05), confirming the success of the hypercholesterolemic diet. However, no statistical differences were noted between the AS and AS＋Endostar groups. Histopathology results revealed that vasa vasorum density and intima-media thickness (IMT) had also increased in the AS group compared with those in the N group (p ＜ 0.05). The Endostar treatment significantly alleviated AS with decreased vasa vasorum density and IMT (AS vs. AS＋Endostar, p ＜ 0.05). Western blot analysis indicated that the expression of VEGF, β-catenin, and TNF-alpha in the atherosclerotic abdominal aorta was considerably reduced by the Endostar treatment. In addition, immunohistochemistry results showed that the angiogenesis markers VEGF and β-catenin were predominately localized in endothelial cells of the adventitial vasa vasorum. The levels of the serum inflammatory markers TNF-alpha, hs-CRP, and IL-6 were markedly higher in the AS group than in the N group (p ＜ 0.05) but showed no marked difference during the Endostar treatment, suggesting that the local inhibition of angiogenesis was not accompanied by a change in serum inflammatory markers and that the inhibitive effect of Endostar on local TNF-alpha expression could be because of the prevention of vasa vasorum neovascularization.
  
  
  CONCLUSIONS
  Our results demonstrated that the Endostar treatment inhibited vasa vasorum neovascularization and AS progression in the experimental porcine model of early AS, supporting the role of vasa vasorum neovascularization in the development of AS and the therapeutic potential of anti-angiogenesis intervention in AS.
authors.affiliation: Department of Cardiology, Zhejiang Traditional Chinese Medical Hospital.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Xu
authors.forename: Wei
authors.initials: W
authors.lastname: Mao
authors.forename: Yueyang
authors.initials: Y
authors.lastname: Chai
authors.forename: Jin
authors.initials: J
authors.lastname: Dai
authors.forename: Qian
authors.initials: Q
authors.lastname: Chen
authors.forename: Lihui
authors.initials: L
authors.lastname: Wang
authors.forename: Qin
authors.initials: Q
authors.lastname: Zhuang
authors.forename: Yongming
authors.initials: Y
authors.lastname: Pan
authors.forename: Minli
authors.initials: M
authors.lastname: Chen
authors.forename: Guibao
authors.initials: G
authors.lastname: Ni
authors.forename: Zhaoquan
authors.initials: Z
authors.lastname: Huang
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001012:Aorta, Abdominal / Q000187:drug effects / Q000473:pathology*; D050197:Atherosclerosis / Q000188:drug therapy* / Q000473:pathology; D015153:Blotting, Western; D004195:Disease Models, Animal; D043169:Endostatins / Q000627:therapeutic use*; D007150:Immunohistochemistry; D008297:Male; D009389:Neovascularization, Pathologic / Q000473:pathology / Q000517:prevention & control*; D011994:Recombinant Proteins; D013552:Swine; D013556:Swine, Miniature; D014651:Vasa Vasorum / Q000473:pathology*
chemical_list: D020533:Angiogenesis Inhibitors; D043169:Endostatins; D011994:Recombinant Proteins; C522911:endostar protein