{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T06:27:26Z","timestamp":1790836046702,"version":"4.1.0"},"reference-count":84,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2021,9,7]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>\n                      Activin receptor-like kinase 1 (ALK1) is an endothelial transmembrane serine threonine kinase receptor for BMP family ligands that plays a critical role in cardiovascular development and pathology. Loss-of-function mutations in the\n                      <jats:italic>ALK1<\/jats:italic>\n                      gene cause type 2 hereditary hemorrhagic telangiectasia, a devastating disorder that leads to arteriovenous malformations. Here, we show that ALK1 controls endothelial cell polarization against the direction of blood flow and flow-induced endothelial migration from veins through capillaries into arterioles.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>\n                      Using Cre lines that recombine in different subsets of arterial, capillary-venous, or endothelial tip cells, we show that capillary-venous\n                      <jats:italic>Alk1<\/jats:italic>\n                      deletion was sufficient to induce arteriovenous malformation formation in the postnatal retina.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      ALK1 deletion impaired capillary-venous endothelial cell polarization against the direction of blood flow in vivo and in vitro. Mechanistically, ALK1-deficient cells exhibited increased integrin signaling interaction with vascular endothelial growth factor receptor 2, which enhanced downstream YAP\/TAZ nuclear translocation. Pharmacologic inhibition of integrin or YAP\/TAZ signaling rescued flow migration coupling and prevented vascular malformations in\n                      <jats:italic>Alk1<\/jats:italic>\n                      -deficient mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>Our study reveals ALK1 as an essential driver of flow-induced endothelial cell migration and identifies loss of flow-migration coupling as a driver of arteriovenous malformation formation in hereditary hemorrhagic telangiectasia disease. Integrin-YAP\/TAZ signaling blockers are new potential targets to prevent vascular malformations in patients with hereditary hemorrhagic telangiectasia.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.120.053047","type":"journal-article","created":{"date-parts":[[2021,6,29]],"date-time":"2021-06-29T05:00:11Z","timestamp":1624942811000},"page":"805-822","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":119,"title":["Defective Flow-Migration Coupling Causes Arteriovenous Malformations in Hereditary Hemorrhagic Telangiectasia"],"prefix":"10.1161","volume":"144","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3671-8618","authenticated-orcid":true,"given":"Hyojin","family":"Park","sequence":"first","affiliation":[{"name":"Cardiovascular Research Center, Department of Internal Medicine (H.P., J.F., M.P., M.C., S.Y., M.A.S., A.E.), Yale University School of Medicine, New Haven, 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