Real-time imaging of de novo arteriovenous malformation in a mouse model of hereditary hemorrhagic telangiectasia
Sung Ok Park, … , Brian S. Sorg, S. Paul Oh
Sung Ok Park, … , Brian S. Sorg, S. Paul Oh
Published October 1, 2009
Citation Information: J Clin Invest. 2009;119(11):3487-3496. https://doi.org/10.1172/JCI39482.
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Technical Advance Vascular biology

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

Sung Ok Park, Mamta Wankhede, Young Jae Lee, Eun-Jung Choi, Naime Fliess, Se-Woon Choe, Seh-Hoon Oh, Glenn Walter, Mohan K. Raizada, Brian S. Sorg, S. Paul Oh

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Figure 1

Endothelial Alk1 deletion from the Alk12loxP allele resulted in postnatal lethality by P5, with AVMs in the brain, lung, and GI tract.

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Endothelial Alk1 deletion from the Alk12loxP allele resulted in postnata...
(A–E) Dissection microscopic views of vascular images of control [L1Cre(–);Alk12loxP/2loxP; A and C] and mutant [L1Cre(+);Alk12loxP/2loxP; B, D, and E] P3 mouse brains with latex dye injected into the left ventricle of the heart. (D and E) Magnified views of blood vessels in the hippocampal area. (E) Asterisks indicate peculiar looping of vessels at the distal tips of arteries shunting to veins. A, artery; V, vein. (F–K) Vascular morphology of control (F, H, and J) and mutant (G, I, and K) P3 lungs. (F and G) Dissection microscopic view of pulmonary veins. Double-headed arrows indicate diameter of pulmonary veins. A dashed circle highlights the area of abnormal tangled vessels, and an arrow indicates looping of a dilated vessel (G). (H and I) Gross views of left lung after Evans blue dye injection via jugular veins. Note bumpy, dilated looping vessels in the mutant lungs (I). (J and K) Scanning electron microgram view of corrosion cast, showing lack of microvessels and presence of numerous dilated looping vessels (asterisks) in the mutant lungs (K). (L–Q) Gross views of small intestines of control (L, N, and P) and mutant (M, O, and Q) P3 mice. AV shunts and abnormal anastomosis was observed by latex dye (O) and corrosion cast (indicated by an arrow with asterisk; Q). Scale bars: 2 mm (A and B); 1 mm (C, D, H, I, and N–Q); 300 μm (E); 500 μm (F, G, L, and M).