A mouse model for hereditary hemorrhagic telangiectasia (HHT) type 2.

Journal Article (Journal Article)

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal-dominant disorder characterized by the age-dependent development of focal arteriovenous malformations and telangiectases. HHT type 2 is caused by loss of function mutations in activin receptor-like kinase 1 (ACVRL1 or ALK1). However, the factors that initiate lesion formation and those that influence disease progression remain unknown. Because heterozygous mice contain the appropriate genotype for an animal model of this disorder, mice heterozygous for a loss-of-function mutation in Acvrl1 were carefully examined for an HHT-like phenotype. These mice developed age-dependent vascular lesions in the skin, extremities, oral cavity and in the internal organs (lung, liver, intestine, spleen and brain), similar to those seen in HHT patients. Major histopathological features of the lesions included thin-walled dilated vessels in close proximity to each other, hemorrhage and fibrosis. Similar to HHT patients, the mice also exhibited gastrointestinal bleeding, as evidenced by positive fecal occult blood tests. An Acvrl1(+/-) mouse with profound liver involvement also displayed a secondary cardiac phenotype, similar to that observed in human patients. The similarity of affected organs, age-dependent penetrance, histological similarity of the lesions and recapitulation of a secondary phenotype suggest that the Acvrl1(+/-) mice are an appropriate animal model for the identification of additional genetic and environmental factors that cause pathology in HHT type 2 patients. In addition, studies utilizing this animal model can yield valuable information on the role of ALK1 in maintenance of adult vascular architecture including arteriovenous identity.

Full Text

Duke Authors

Cited Authors

  • Srinivasan, S; Hanes, MA; Dickens, T; Porteous, MEM; Oh, SP; Hale, LP; Marchuk, DA

Published Date

  • March 1, 2003

Published In

Volume / Issue

  • 12 / 5

Start / End Page

  • 473 - 482

PubMed ID

  • 12588795

International Standard Serial Number (ISSN)

  • 0964-6906

Digital Object Identifier (DOI)

  • 10.1093/hmg/ddg050


  • eng

Conference Location

  • England