Somatic mutations in arteriovenous malformations in hereditary hemorrhagic telangiectasia support a bi-allelic two-hit mutation mechanism of pathogenesis

DeBose-Scarlett, Evon; Ressler, Andrew K.; Gallione, Carol J.; Sapisochin Cantis, Gonzalo; Friday, Cassi; Weinsheimer, Shantel; Schimmel, Katharina; Spiekerkoetter, Edda; Kim, Helen; Gossage, James R.; Faughnan, Marie E.; Marchuk, Douglas A.

doi:10.1016/j.ajhg.2024.08.020

The American Journal of Human Genetics

2024

DOI: 10.1016/j.ajhg.2024.08.020

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Somatic mutations in arteriovenous malformations in hereditary hemorrhagic telangiectasia support a bi-allelic two-hit mutation mechanism of pathogenesis

Evon DeBose-Scarlett,

Andrew K. Ressler,

Carol J. Gallione

et al.

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2024

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Arterial endothelial deletion of hereditary hemorrhagic telangiectasia 2/Alk1causes epistaxis and cerebral microhemorrhage with aberrant arteries and defective smooth muscle coverage

Zhang,

Jacobs,

Raygor

et al. 2024

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Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant vascular disorder with presentations including severe nose bleeding and microhemorrhage in brains. Despite being the second most common inherited bleeding disorder, the pathophysiological mechanism underlying HHT-associated hemorrhage is poorly understood. Mutations in activin receptor-like kinase 1 (ALK1) gene cause HHT type 2. HHT pathogenesis is thought to follow a Knudsonian two-hit model, requiring a second somatic mutation for lesion formation. We hypothesize that somatic mutation ofAlk1in arterial endothelial cells (AECs) leads to arterial defects and hemorrhage. Here, we investigate the effects of Alk1 mutation in AECs in mice, usingBmx(PAC)-CreERT2-mediated postnatal somatic mutation. We mutatedAlk1in primarily AECs and found that somatic arterial endothelial mutation ofAlk1is sufficient to induce spontaneous epistaxis and multifocal cerebral microhemorrhage. Interestingly, this bleeding occurred in the presence of tortuous and enlarged blood vessels, loss of arterial molecular markerEfnb2, disorganization of vascular smooth muscle, and impaired vasoregulation. Our data suggest that arterial endothelial mutation ofAlk1causing reduced arterial identity and disruption of vascular smooth muscle cell coverage is a plausible molecular mechanism for HHT-associated severe epistaxis. This work provides the first evidence that somatic ALK1 loss in AECs can cause hemorrhagic vascular lesions, offering a novel preclinical model critically needed for studying HHT-associated epistaxis, and delineating an arterial mechanism to HHT pathophysiology.

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Arterial endothelial deletion of hereditary hemorrhagic telangiectasia 2/Alk1causes epistaxis and cerebral microhemorrhage with aberrant arteries and defective smooth muscle coverage

Zhang,

Jacobs,

Raygor

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

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Somatic mutations in arteriovenous malformations in hereditary hemorrhagic telangiectasia support a bi-allelic two-hit mutation mechanism of pathogenesis

Cited by 1 publication

References 57 publications

Arterial endothelial deletion of hereditary hemorrhagic telangiectasia 2/Alk1causes epistaxis and cerebral microhemorrhage with aberrant arteries and defective smooth muscle coverage

Arterial endothelial deletion of hereditary hemorrhagic telangiectasia 2/Alk1causes epistaxis and cerebral microhemorrhage with aberrant arteries and defective smooth muscle coverage

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