Eva M Garrido-Martin1, Ha-Long Nguyen1, Tyler A Cunningham1, Se-Woon Choe1, Zhihua Jiang1, Helen M Arthur1, Young-Jae Lee1, S Paul Oh2. 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.
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.
Authors: Anthony Cannavicci; Qiuwang Zhang; Si-Cheng Dai; Marie E Faughnan; Michael J B Kutryk Journal: Can J Physiol Pharmacol Date: 2018-12-04 Impact factor: 2.273
Authors: Daniel A Snellings; Carol J Gallione; Dewi S Clark; Nicholas T Vozoris; Marie E Faughnan; Douglas A Marchuk Journal: Am J Hum Genet Date: 2019-10-17 Impact factor: 11.025