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

• Published in: The Journal of clinical investigation Vol. 119; no. 11; pp. 3487 - 3496
• Main Authors: Park, Sung Ok, Wankhede, Mamta, Lee, Young Jae, Choi, Eun-Jung, Fliess, Naime, Choe, Se-Woon, Oh, Seh-Hoon, Walter, Glenn, Raizada, Mohan K., Sorg, Brian S., Oh, S. Paul
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.11.2009
• Subjects: Activin Receptors, Type I - genetics; Animals; Arteriovenous malformations; Arteriovenous Malformations - diagnosis; Arteriovenous Malformations - ultrastructure; Biomedical research; Blood vessels; Blood Vessels - embryology; Blood Vessels - injuries; Care and treatment; Diagnostic Imaging - methods; Disease Models, Animal; Epistaxis; Female; Gene mutations; Genes; Genetic aspects; Health aspects; Homeostasis; Kinases; Male; Mice; Mutation; Physiology; Risk factors; Signal transduction; Technical Advance; Telangiectasia, Hereditary Hemorrhagic; Telangiectasia, Hereditary Hemorrhagic - genetics; Telangiectasia, Hereditary Hemorrhagic - pathology; Veins & arteries; United States
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI39482

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.