Angiogenesis Inhibitor, Endostar, Prevents Vasa Vasorum Neovascularization in a Swine Atherosclerosis Model

Abstract

Aim: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, -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 -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 antiangiogenesis intervention in AS.

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

“…In preclinical models, it has been demonstrated that pro‐angiogenic strategies augment atherosclerotic plaque growth and vascular inflammation, whereas anti‐angiogenic strategies inhibit atherosclerosis . Previously, we have shown that lesions induced by vein grafting in atherosclerosis‐prone mice display profound plaque neovessels and intraplaque haemorrhage .…”

Integrin signaling in atherosclerosis

“…Endostatin, a cleavage product of collagen XVIII, limits angiogenesis through inhibitory interactions with the endothelial integrins α5β1 and αvβ3 [84]. Endostatin treatment limited both plaque angiogenesis and neointimal area in hypercholesterolemic mice [77], and the endostatin-derivative Endostar reduces vasa vasorum density in hypercholesterolemic mini pigs associated with reduced intimal-medial thickness [85]. However, it is not clear from these studies that the reduction in angiogenesis caused the reduction in plaque area, as endostatin may affect other integrin-dependent functions.…”

Association of Circulating Levels of ADMA with Carotid Intima-Media Thickness in Patients with CKD: a Systematic Review and Meta-Analysis

“…Endothelial dysfunction was a key factor in the progression of atherosclerotic cardiovascular disease [5]. The integrity of endothelial function was closely related to the stable condition of nitric oxide system [6].…”