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Arterioscler Thromb Vasc Biol. 2014 Oct;34(10):2232-6. doi: 10.1161/ATVBAHA.114.303984. Epub 2014 Jul 31.

Common and distinctive pathogenetic features of arteriovenous malformations in hereditary hemorrhagic telangiectasia 1 and hereditary hemorrhagic telangiectasia 2 animal models--brief report.

Author information

1
From the Department of Physiology and Functional Genomics (E.M.G.-M., H.-L.N., T.A.C., S.-w.C., S.P.O.) and Department of Surgery (Z.J.), University of Florida, Gainesville; Department of Biomedical Engineering, Tongmyong University, Busan, Republic of Korea (S.-w.C.); Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom (H.M.A.); and Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Republic of Korea (Y.-J.L., S.P.O.).
2
From the Department of Physiology and Functional Genomics (E.M.G.-M., H.-L.N., T.A.C., S.-w.C., S.P.O.) and Department of Surgery (Z.J.), University of Florida, Gainesville; Department of Biomedical Engineering, Tongmyong University, Busan, Republic of Korea (S.-w.C.); Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom (H.M.A.); and Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Republic of Korea (Y.-J.L., S.P.O.). ohp@ufl.edu.

Abstract

OBJECTIVE:

Hereditary hemorrhagic telangiectasia is a genetic disorder characterized by visceral and mucocutaneous arteriovenous malformations (AVMs). Clinically indistinguishable hereditary hemorrhagic telangiectasia 1 and hereditary hemorrhagic telangiectasia 2 are caused by mutations in ENG and ALK1, respectively. In this study, we have compared the development of visceral and mucocutaneous AVMs in adult stages between Eng- and Alk1-inducible knockout (iKO) models.

APPROACH AND RESULTS:

Eng or Alk1 were deleted from either vascular endothelial cells (ECs) or smooth muscle cells in adult stages using Scl-CreER and Myh11-CreER lines, respectively. Latex perfusion and intravital spectral imaging in a dorsal skinfold window chamber system were used to visualize remodeling vasculature during AVM formation. Global Eng deletion resulted in lethality with visceral AVMs and wound-induced skin AVMs. Deletion of Alk1 or Eng in ECs, but not in smooth muscle cells, resulted in wound-induced skin AVMs. Visceral AVMs were observed in EC-specific Alk1-iKO but not in Eng-iKO. Intravital spectral imaging revealed that Eng-iKO model exhibited more dynamic processes for AVM development when compared with Alk1-iKO model.

CONCLUSIONS:

Both Alk1- and Eng-deficient models require a secondary insult, such as wounding, and ECs are the primary cell type responsible for the pathogenesis. However, Alk1 but not Eng deletion in ECs results in visceral AVMs.

KEYWORDS:

Alk1 protein, mouse; arteriovenous malformations; endoglin protein, mouse; endothelial cells; myocytes, smooth muscle; telangiectasia, hereditary hemorrhagic

PMID:
25082229
DOI:
10.1161/ATVBAHA.114.303984
[Indexed for MEDLINE]

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