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Since proteins from all 3 HHT genes are components of signal transduction of TGF-\u03b2 (transforming growth factor \u03b2) family members, it has been hypothesized that HHT is a disease caused by defects in the ENG-ALK1-SMAD4 linear signaling. However, in vivo evidence supporting this hypothesis is scarce.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Objective:<\/jats:title>\n            <jats:p>We tested this hypothesis and investigated the therapeutic effects and potential risks of induced-ALK1 or -ENG overexpression (OE) for HHT.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods and Results:<\/jats:title>\n            <jats:p>\n              We generated a novel mouse allele (ROSA26\n              <jats:sup>Alk1<\/jats:sup>\n              ) in which HA (human influenza hemagglutinin)-tagged ALK1 and bicistronic eGFP expression are induced by Cre activity. We examined whether ALK1-OE using the ROSA26\n              <jats:sup>Alk1<\/jats:sup>\n              allele could suppress the development of arteriovenous malformations (AVMs) in wounded adult skin and developing retinas of\n              <jats:italic>Alk1<\/jats:italic>\n              - and\n              <jats:italic>Eng<\/jats:italic>\n              -inducible knockout (iKO) mice. We also used a similar approach to investigate whether ENG-OE could rescue AVMs. Biochemical and immunofluorescence analyses confirmed the Cre-dependent OE of the ALK1-HA transgene. We could not detect any pathological signs in ALK1-OE mice up to 3 months after induction. ALK1-OE prevented the development of retinal AVMs and wound-induced skin AVMs in\n              <jats:italic>Eng<\/jats:italic>\n              -iKO as well as\n              <jats:italic>Alk1<\/jats:italic>\n              -iKO mice. ALK1-OE normalized expression of SMAD and NOTCH target genes in ENG-deficient endothelial cells (ECs) and restored the effect of BMP9 (bone morphogenetic protein 9) on suppression of phosphor-AKT levels in these endothelial cells. On the other hand, ENG-OE could not inhibit the AVM development in\n              <jats:italic>Alk1<\/jats:italic>\n              -iKO models.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>These data support the notion that ENG and ALK1 form a linear signaling pathway for the formation of a proper arteriovenous network during angiogenesis. We suggest that ALK1 OE or activation can be an effective therapeutic strategy for HHT. Further research is required to study whether this therapy could be translated into treatment for humans.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circresaha.119.316267","type":"journal-article","created":{"date-parts":[[2020,7,31]],"date-time":"2020-07-31T09:00:23Z","timestamp":1596186023000},"page":"1122-1137","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":49,"title":["Overexpression of Activin Receptor-Like Kinase 1 in Endothelial Cells Suppresses Development of Arteriovenous Malformations in Mouse Models of Hereditary Hemorrhagic Telangiectasia"],"prefix":"10.1161","volume":"127","author":[{"given":"Yong","family":"Hwan Kim","sequence":"first","affiliation":[{"name":"Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville (Y.H.K., S.-w.C., S.P.O.)."},{"name":"Department of Neurobiology, Barrow Neurological Institute, Phoenix, AZ (Y.H.K., S.P.O.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phuong-Nhung","family":"Vu","sequence":"additional","affiliation":[{"name":"Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Republic of Korea (N.V.P., Y.J.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7298-4147","authenticated-orcid":true,"given":"Se-woon","family":"Choe","sequence":"additional","affiliation":[{"name":"Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville (Y.H.K., S.-w.C., S.P.O.)."},{"name":"Department of Medical IT Convergence Engineering, Kumoh National Institute of Technology, Gumi, Republic of Korea (S.-w.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang-Jin","family":"Jeon","sequence":"additional","affiliation":[{"name":"Department of Biology, College of Natural Sciences, Kyungpook National University, Daegu, Korea (C.J.J.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen M.","family":"Arthur","sequence":"additional","affiliation":[{"name":"Institute of Genetic Medicine, Newcastle University, United Kingdom (H.M.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Calvin P.H.","family":"Vary","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough (C.P.V.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3841-1994","authenticated-orcid":true,"given":"Young Jae","family":"Lee","sequence":"additional","affiliation":[{"name":"Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Republic of Korea (N.V.P., Y.J.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. 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