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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

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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 5

Vascular remodeling during development of wound-induced de novo AVM.

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Vascular remodeling during development of wound-induced de novo AVM.
A l...
A light-microscopic view and the corresponding Hb(O2) pseudocolor map of vascular morphogenesis during wound healing for 8 days in the mutant. Arteries are readily distinguishable from veins by high O2 levels days 1–5 after wounding (A–D). Early stages of AV shunts (dotted circles in B and D) were detected as early as day 3. White arrows in B, C, and E indicate veins containing high Hb(O2) levels. Blue arrows in C and F indicate veins at downstream of the AV shunts, showing dilated vascular morphologies. By day 6 (E–G), Hb(O2) levels in the veins draining from the AV shunts are as high as those in the arteries feeding to AV shunts. It is noteworthy that there were signs of bleeding where AV shunts are established (red arrows in B–D). Ratio of Hb(O2) saturation of veins and arteries in the mutants was elevated as wound healing progressed, while that in control mice remained unchanged (H). Error bars in H indicate SD. Scale bar in A: 1 mm.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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