VEGF Neutralization Can Prevent and Normalize Arteriovenous Malformations in an Animal Model for Hereditary Hemorrhagic Telangiectasia 2

Angiogenesis. 2014 Oct;17(4):823-830. doi: 10.1007/s10456-014-9436-3. Epub 2014 Jun 24.

Abstract

Arteriovenous malformation (AVM) refers to a vascular anomaly where arteries and veins are directly connected through a complex, tangled web of abnormal AV fistulae without a normal capillary network. Hereditary hemorrhagic telangiectasia (HHT) types 1 and 2 arise from heterozygous mutations in endoglin (ENG) and activin receptor-like kinase 1 (ALK1), respectively. HHT patients possess AVMs in various organs, and telangiectases (small AVMs) along the mucocutaneous surface. Understanding why and how AVMs develop is crucial for developing therapies to inhibit the formation, growth, or maintenance of AVMs in HHT patients. Previously, we have shown that secondary factors such as wounding are required for Alk1-deficient vessels to develop skin AVMs. Here, we present evidences that AVMs establish from nascent arteries and veins rather than from remodeling of a preexistent capillary network in the wound-induced skin AVM model. We also show that VEGF can mimic the wound effect on skin AVM formation, and VEGF-neutralizing antibody can prevent skin AVM formation and ameliorate internal bleeding in Alk1-deficient adult mice. With topical applications at different stages of AVM development, we demonstrate that the VEGF blockade can prevent the formation of AVM and cease the progression of AVM development. Taken together, the presented experimental model is an invaluable system for precise molecular mechanism of action of VEGF blockades as well as for preclinical screening of drug candidates for epistaxis and gastrointestinal bleedings.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Neutralizing / pharmacology
  • Arteriovenous Malformations / metabolism*
  • Brain / pathology
  • Disease Models, Animal
  • Disease Progression
  • Heterozygote
  • Mice
  • Mice, Knockout
  • Mutation
  • Neovascularization, Pathologic
  • Telangiectasia, Hereditary Hemorrhagic / metabolism*
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors*
  • Vascular Endothelial Growth Factor A / metabolism
  • Wound Healing

Substances

  • Antibodies, Neutralizing
  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A, mouse