{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T11:46:11Z","timestamp":1791805571334,"version":"4.3.4"},"reference-count":50,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"21","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2018,11,20]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>\n                      Hereditary hemorrhagic telangiectasia (HHT) is an inherited vascular disorder that causes arteriovenous malformations (AVMs). Mutations in the genes encoding Endoglin (\n                      <jats:italic>ENG<\/jats:italic>\n                      ) and activin-receptor-like kinase 1 (\n                      <jats:italic>AVCRL1<\/jats:italic>\n                      encoding ALK1) cause HHT type 1 and 2, respectively. Mutations in the\n                      <jats:italic>SMAD4<\/jats:italic>\n                      gene are present in families with juvenile polyposis-HHT syndrome that involves AVMs. SMAD4 is a downstream effector of transforming growth factor-\u03b2 (TGF\u03b2)\/bone morphogenetic protein (BMP) family ligands that signal via activin-like kinase receptors (ALKs). Ligand-neutralizing antibodies or inducible, endothelial-specific\n                      <jats:italic>Alk1<\/jats:italic>\n                      deletion induce AVMs in mouse models as a result of increased PI3K (phosphatidylinositol 3-kinase)\/AKT (protein kinase B) signaling. Here we addressed if SMAD4 was required for BMP9-ALK1 effects on PI3K\/AKT pathway activation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>\n                      The authors generated tamoxifen-inducible, postnatal, endothelial-specific\n                      <jats:italic>Smad4<\/jats:italic>\n                      mutant mice (\n                      <jats:italic>Smad4<\/jats:italic>\n                      <jats:sup>i\u0394EC<\/jats:sup>\n                      ).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      We found that loss of endothelial\n                      <jats:italic>Smad4<\/jats:italic>\n                      resulted in AVM formation and lethality. AVMs formed in regions with high blood flow in developing retinas and other tissues. Mechanistically, BMP9 signaling antagonized flow-induced AKT activation in an ALK1- and SMAD4-dependent manner.\n                      <jats:italic>Smad4<\/jats:italic>\n                      <jats:sup>i\u0394EC<\/jats:sup>\n                      endothelial cells in AVMs displayed increased PI3K\/AKT signaling, and pharmacological PI3K inhibitors or endothelial\n                      <jats:italic>Akt1<\/jats:italic>\n                      deletion both rescued AVM formation in\n                      <jats:italic>Smad4<\/jats:italic>\n                      <jats:sup>i\u0394EC<\/jats:sup>\n                      mice. BMP9-induced SMAD4 inhibited casein kinase 2 (\n                      <jats:italic>CK2<\/jats:italic>\n                      ) transcription, in turn limiting PTEN phosphorylation and AKT activation. Consequently, CK2 inhibition prevented AVM formation in\n                      <jats:italic>Smad4<\/jats:italic>\n                      <jats:sup>i\u0394EC<\/jats:sup>\n                      mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>\n                      Our study reveals SMAD4 as an essential effector of BMP9-10\/ALK1 signaling that affects AVM pathogenesis via regulation of\n                      <jats:italic>CK2<\/jats:italic>\n                      expression and PI3K\/AKT1 activation.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.118.033842","type":"journal-article","created":{"date-parts":[[2018,7,5]],"date-time":"2018-07-05T05:25:16Z","timestamp":1530768316000},"page":"2379-2394","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":136,"title":["SMAD4 Prevents Flow Induced Arteriovenous Malformations by Inhibiting Casein Kinase 2"],"prefix":"10.1161","volume":"138","author":[{"given":"Roxana","family":"Ola","sequence":"first","affiliation":[{"name":"Cardiovascular Research Center, Department of Internal Medicine (R.O., S.H.K., F.Z., G.G., R.C., K.M., A.D., A.E.), Yale University School of Medicine, New Haven, Connecticut."},{"name":"Functional Genomics, Proteomics and Experimental Pathology Department, Prof. Dr. I. Chiricuta Oncology Institute, Cluj-Napoca, Romania (R.O.)."},{"name":"Research Center for Functional Genomics, Biomedicine and Translational Medicine, I. Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania (R.O.)."},{"name":"Department of Basic, Preventive and Clinical Science, University of Transylvania, Brasov, Romania (R.O.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandrine H.","family":"K\u00fcnzel","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center, Department of Internal Medicine (R.O., S.H.K., F.Z., G.G., R.C., K.M., A.D., A.E.), Yale University School of Medicine, New Haven, Connecticut."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center, Department of Internal Medicine (R.O., S.H.K., F.Z., G.G., R.C., K.M., A.D., A.E.), Yale University School of Medicine, New Haven, Connecticut."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gael","family":"Genet","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center, Department of Internal Medicine (R.O., S.H.K., F.Z., G.G., R.C., K.M., A.D., A.E.), Yale University School of Medicine, New Haven, Connecticut."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raja","family":"Chakraborty","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center, Department of Internal Medicine (R.O., S.H.K., F.Z., G.G., R.C., K.M., A.D., A.E.), Yale University School of Medicine, New Haven, Connecticut."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurence","family":"Pibouin-Fragner","sequence":"additional","affiliation":[{"name":"Inserm U970, Paris Cardiovascular Research Center, Paris, France (L.P-F., A.E.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen","family":"Martin","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center, Department of Internal Medicine (R.O., S.H.K., F.Z., G.G., R.C., K.M., A.D., A.E.), Yale University School of Medicine, New Haven, Connecticut."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Sessa","sequence":"additional","affiliation":[{"name":"Vascular Biology and Therapeutics Program, Department of Pharmacology (W.S.), Yale University School of Medicine, New Haven, Connecticut."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandre","family":"Dubrac","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center, Department of Internal Medicine (R.O., S.H.K., F.Z., G.G., R.C., K.M., A.D., A.E.), Yale University School of Medicine, New Haven, Connecticut."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Eichmann","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center, Department of Internal Medicine (R.O., S.H.K., F.Z., G.G., R.C., K.M., A.D., A.E.), Yale University School of Medicine, New Haven, Connecticut."},{"name":"Department of Cellular and Molecular Physiology (A.E.), Yale University School of Medicine, New Haven, Connecticut."},{"name":"Inserm U970, Paris Cardiovascular Research Center, Paris, France (L.P-F., A.E.)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.blre.2010.07.001"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1098-1004(1998)11:4<286::AID-HUMU6>3.0.CO;2-B"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng0696-189"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1097\/GIM.0b013e3182136d32"},{"key":"e_1_3_3_6_2","doi-asserted-by":"crossref","first-page":"a031989","DOI":"10.1101\/cshperspect.a031989","article-title":"Bone morphogenetic proteins in vascular homeostasis and disease.","volume":"10","author":"Goumans MJ","year":"2017","unstructured":"Goumans, MJ, Zwijsen, A, Ten Dijke, P and Bailly, S. 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