title: Real-time imaging of de novo arteriovenous malformation in a mouse model of hereditary hemorrhagic telangiectasia.
abstract: 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.
authors.affiliation: Department of Physiology and Functional Genomics, College of Medicine, University of Florida, 1376 Mowry Road, Room 456, Gainesville, Florida 32610, USA.
authors.forename: Sung Ok
authors.initials: SO
authors.lastname: Park
authors.forename: Mamta
authors.initials: M
authors.lastname: Wankhede
authors.forename: Young Jae
authors.initials: YJ
authors.lastname: Lee
authors.forename: Eun-Jung
authors.initials: EJ
authors.lastname: Choi
authors.forename: Naime
authors.initials: N
authors.lastname: Fliess
authors.forename: Se-Woon
authors.initials: SW
authors.lastname: Choe
authors.forename: Seh-Hoon
authors.initials: SH
authors.lastname: Oh
authors.forename: Glenn
authors.initials: G
authors.lastname: Walter
authors.forename: Mohan K
authors.initials: MK
authors.lastname: Raizada
authors.forename: Brian S
authors.initials: BS
authors.lastname: Sorg
authors.forename: S Paul
authors.initials: SP
authors.lastname: Oh
mesh_terms: D030201:Activin Receptors, Type I / Q000235:genetics; D030301:Activin Receptors, Type II; D000818:Animals; D001165:Arteriovenous Malformations / Q000175:diagnosis* / Q000648:ultrastructure; D001808:Blood Vessels / Q000196:embryology / Q000293:injuries; D003952:Diagnostic Imaging / Q000379:methods*; D004195:Disease Models, Animal; D005260:Female; D006706:Homeostasis; D008297:Male; D051379:Mice; D009154:Mutation; D013683:Telangiectasia, Hereditary Hemorrhagic / Q000235:genetics / Q000473:pathology*
chemical_list: D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II; C498931:Acvrl1 protein, mouse