Real-time imaging of de novo arteriovenous malformation in a mouse model of hereditary hemorrhagic telangiectasia

J Clin Invest. 2009 Nov;119(11):3487-96. doi: 10.1172/JCI39482. Epub 2009 Oct 1.


Arteriovenous malformations (AVMs) are vascular anomalies where arteries and veins are directly connected through a complex, tangled web of abnormal arteries and veins instead of a normal capillary network. AVMs in the brain, lung, and visceral organs, including the liver and gastrointestinal tract, result in considerable morbidity and mortality. AVMs are the underlying cause of three major clinical symptoms of a genetic vascular dysplasia termed hereditary hemorrhagic telangiectasia (HHT), which is characterized by recurrent nosebleeds, mucocutaneous telangiectases, and visceral AVMs and caused by mutations in one of several genes, including activin receptor-like kinase 1 (ALK1). It remains unknown why and how selective blood vessels form AVMs, and there have been technical limitations to observing the initial stages of AVM formation. Here we present in vivo evidence that physiological or environmental factors such as wounds in addition to the genetic ablation are required for Alk1-deficient vessels to develop to AVMs in adult mice. Using the dorsal skinfold window chamber system, we have demonstrated for what we believe to be the first time the entire course of AVM formation in subdermal blood vessels by using intravital bright-field images, hyperspectral imaging, fluorescence recordings of direct arterial flow through the AV shunts, and vascular casting techniques. We believe our data provide novel insights into the pathogenetic mechanisms of HHT and potential therapeutic approaches.

Publication types

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

MeSH terms

  • Activin Receptors, Type I / genetics
  • Activin Receptors, Type II
  • Animals
  • Arteriovenous Malformations / diagnosis*
  • Arteriovenous Malformations / ultrastructure
  • Blood Vessels / embryology
  • Blood Vessels / injuries
  • Diagnostic Imaging / methods*
  • Disease Models, Animal
  • Female
  • Homeostasis
  • Male
  • Mice
  • Mutation
  • Telangiectasia, Hereditary Hemorrhagic / genetics
  • Telangiectasia, Hereditary Hemorrhagic / pathology*


  • Activin Receptors, Type I
  • Activin Receptors, Type II
  • Acvrl1 protein, mouse