Vasa vasorum anti-angiogenesis through H₂O₂, HIF-1α, NF-κB, and iNOS inhibition by mangosteen pericarp ethanolic extract (Garcinia mangostana Linn) in hypercholesterol-diet-given Rattus norvegicus Wistar strain

Vasc Health Risk Manag. 2014 Aug 21;10:523-31. doi: 10.2147/VHRM.S61736. eCollection 2014.


Background: Oxidative stress in atherosclerosis produces H2O2 and triggers the activation of nuclear factor kappa beta (NF-κB) and increase of inducible nitric oxide synthase (iNOS). The formation of vasa vasorum occurs in atherosclerosis. Vasa vasorum angiogenesis is mediated by VEGFR-1 and upregulated by hypoxia-inducible factor-1α (HIF-1α). The newly formed vasa vasorum are fragile and immature and thus increase plaque instability. It is necessary to control vasa vasorum angiogenesis by using mangosteen pericarp antioxidant. This study aims to demonstrate that mangosteen pericarp ethanolic extract can act as vasa vasorum anti-angiogenesis through H2O2, HIF-1α, NF-κB, and iNOS inhibition in rats given a hypercholesterol diet.

Methods: This was a true experimental laboratory, in vivo posttest with control group design, with 20 Rattus norvegicus Wistar strain rats divided into five groups (normal group, hypercholesterol group, and hypercholesterol groups with certain doses of mangosteen pericarp ethanolic extract: 200, 400, and 800 mg/kg body weight). The parameters of this study were H2O2 measured by using colorimetric analysis, as well as NF-κB, iNOS, and HIF-1α, which were measured by using immunofluorescence double staining and observed with a confocal laser scanning microscope in aortic smooth muscle cell. The angiogenesis of vasa vasorum was quantified from VEGFR-1 level in aortic tissue and confirmed with hematoxylin and eosin staining.

Results: Analysis of variance test and Pearson's correlation coefficient showed mangosteen pericarp ethanolic extract had a significant effect (P<0.05) in decreasing vasa vasorum angiogenesis through H2O2, HIF-1α, NF-κB, and iNOS inhibition in hypercholesterol-diet-given R. norvegicus Wistar strain.

Conclusion: Mangosteen pericarp ethanolic extract 800 mg/kg body weight is proven to decrease vasa vasorum angiogenesis. Similar studies with other inflammatory parameters are encouraged to clarify the mechanism of vasa vasorum angiogenesis inhibition by mangosteen pericarp ethanolic extract.

Keywords: H2O2; HIF-1α; NF-κB; hypercholesterol; mangosteen pericarp ethanolic extract; vasa vasorum angiogenesis.

MeSH terms

  • Angiogenesis Inhibitors / isolation & purification
  • Angiogenesis Inhibitors / pharmacology*
  • Animals
  • Aortic Diseases / etiology
  • Aortic Diseases / metabolism
  • Aortic Diseases / pathology
  • Aortic Diseases / prevention & control*
  • Atherosclerosis / etiology
  • Atherosclerosis / metabolism
  • Atherosclerosis / pathology
  • Atherosclerosis / prevention & control*
  • Cholesterol, Dietary*
  • Diet, High-Fat*
  • Disease Models, Animal
  • Down-Regulation
  • Ethanol / chemistry*
  • Garcinia mangostana* / chemistry
  • Hydrogen Peroxide / metabolism*
  • Hypercholesterolemia / drug therapy*
  • Hypercholesterolemia / etiology
  • Hypercholesterolemia / metabolism
  • Hypercholesterolemia / pathology
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Male
  • NF-kappa B / metabolism*
  • Neovascularization, Pathologic*
  • Nitric Oxide Synthase Type II / metabolism*
  • Phytotherapy
  • Plant Extracts / isolation & purification
  • Plant Extracts / pharmacology*
  • Plants, Medicinal
  • Rats, Wistar
  • Signal Transduction / drug effects
  • Solvents / chemistry*
  • Vasa Vasorum / drug effects*
  • Vasa Vasorum / metabolism
  • Vasa Vasorum / pathology


  • Angiogenesis Inhibitors
  • Cholesterol, Dietary
  • Hif1a protein, rat
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • NF-kappa B
  • Plant Extracts
  • Solvents
  • Ethanol
  • Hydrogen Peroxide
  • Nitric Oxide Synthase Type II
  • Nos2 protein, rat