{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T23:47:55Z","timestamp":1792712875654,"version":"4.5.0"},"reference-count":12,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Stroke"],"published-print":{"date-parts":[[2014,5]]},"abstract":"<jats:sec>\n            <jats:title>Background and Purpose\u2014<\/jats:title>\n            <jats:p>\n              The Heart of Glass (HEG) receptor binds KRIT1 and functions with KRIT1, CCM2, and PDCD10 in a common signaling pathway required for heart and vascular development. Mutations in\n              <jats:italic>KRIT1, CCM2<\/jats:italic>\n              , and\n              <jats:italic>PDCD10<\/jats:italic>\n              also underlie human cerebral cavernous malformation (CCM) and postnatal loss of these genes in the mouse endothelium results in rapid CCM formation. Here, we test the role of HEG in CCM formation in mice and in humans.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods\u2014<\/jats:title>\n            <jats:p>\n              We constitutively or conditionally deleted\n              <jats:italic>Heg<\/jats:italic>\n              and\n              <jats:italic>Ccm2<\/jats:italic>\n              genes in genetically modified mice. Mouse embryos, brain, and retina tissues were analyzed to assess CCM lesion formation.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results\u2014<\/jats:title>\n            <jats:p>\n              In postnatal mice, CCMs form with\n              <jats:italic>Ccm2<\/jats:italic>\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\n              but not with\n              <jats:italic>Heg<\/jats:italic>\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\n              or\n              <jats:italic>Heg<\/jats:italic>\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\n              ;\n              <jats:italic>Ccm2<\/jats:italic>\n              <jats:sup>+\/-<\/jats:sup>\n              endothelial cells. Consistent with these findings, human patients with CCM who lack exonic mutations in\n              <jats:italic>KRIT1, CCM2<\/jats:italic>\n              , or\n              <jats:italic>PDCD10<\/jats:italic>\n              do not have mutations in\n              <jats:italic>HEG<\/jats:italic>\n              .\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\u2014<\/jats:title>\n            <jats:p>These findings suggest that the HEG-CCM signaling functions during cardiovascular development and growth, whereas CCMs arise because of loss of HEG-independent CCM signaling in the endothelium of the central nervous system after birth.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/strokeaha.114.004809","type":"journal-article","created":{"date-parts":[[2014,3,19]],"date-time":"2014-03-19T04:45:07Z","timestamp":1395204307000},"page":"1505-1509","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":23,"title":["Cerebral Cavernous Malformations Arise Independent of the Heart of Glass Receptor"],"prefix":"10.1161","volume":"45","author":[{"given":"Xiangjian","family":"Zheng","sequence":"first","affiliation":[{"name":"From the Department of Medicine and Cardiovascular Institute (X.Z., A.T.T., W.P., J.Y., M.L.K.), and Department of Pathology (B.K.), University of Pennsylvania, Philadelphia, PA; Department of Pediatric Cardiology, Children's Hospital of Philadelphia, Philadelphia, PA (C.D.M.); Department of G\u00e9n\u00e9tique des Maladies Vasculaires, INSERM, U740, Paris, France (F.R., F.B., E.T.-L.); Universit\u00e9 Paris Diderot, Sorbonne Paris Cit\u00e9, G\u00e9n\u00e9tique des Maladies Vasculaires UMR-S740, Paris, France (E.T.-L.); AP-HP,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florence","family":"Riant","sequence":"additional","affiliation":[{"name":"From the Department of Medicine and Cardiovascular Institute (X.Z., A.T.T., W.P., J.Y., M.L.K.), and Department of Pathology (B.K.), University of Pennsylvania, Philadelphia, PA; Department of Pediatric Cardiology, Children's Hospital of Philadelphia, Philadelphia, PA (C.D.M.); Department of G\u00e9n\u00e9tique des Maladies Vasculaires, INSERM, U740, Paris, France (F.R., F.B., E.T.-L.); Universit\u00e9 Paris Diderot, Sorbonne Paris Cit\u00e9, G\u00e9n\u00e9tique des Maladies Vasculaires UMR-S740, Paris, France (E.T.-L.); AP-HP,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fran\u00e7oise","family":"Bergametti","sequence":"additional","affiliation":[{"name":"From the Department of Medicine and Cardiovascular Institute (X.Z., A.T.T., W.P., J.Y., M.L.K.), and Department of Pathology (B.K.), University of Pennsylvania, Philadelphia, PA; Department of Pediatric Cardiology, Children's Hospital of Philadelphia, Philadelphia, PA (C.D.M.); Department of G\u00e9n\u00e9tique des Maladies Vasculaires, INSERM, U740, Paris, France (F.R., F.B., E.T.-L.); Universit\u00e9 Paris Diderot, Sorbonne Paris Cit\u00e9, G\u00e9n\u00e9tique des Maladies Vasculaires UMR-S740, Paris, France (E.T.-L.); AP-HP,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cynthia D.","family":"Myers","sequence":"additional","affiliation":[{"name":"From the Department of Medicine and Cardiovascular Institute (X.Z., A.T.T., W.P., J.Y., M.L.K.), and Department of Pathology (B.K.), University of Pennsylvania, Philadelphia, PA; Department of Pediatric Cardiology, Children's Hospital of Philadelphia, Philadelphia, PA (C.D.M.); Department of G\u00e9n\u00e9tique des Maladies Vasculaires, INSERM, U740, Paris, France (F.R., F.B., E.T.-L.); Universit\u00e9 Paris Diderot, Sorbonne Paris Cit\u00e9, G\u00e9n\u00e9tique des Maladies Vasculaires UMR-S740, Paris, France (E.T.-L.); AP-HP,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan T.","family":"Tang","sequence":"additional","affiliation":[{"name":"From the Department of Medicine and Cardiovascular Institute (X.Z., A.T.T., W.P., J.Y., M.L.K.), and Department of Pathology (B.K.), University of Pennsylvania, Philadelphia, PA; Department of Pediatric Cardiology, Children's Hospital of Philadelphia, Philadelphia, PA (C.D.M.); Department of G\u00e9n\u00e9tique des Maladies Vasculaires, INSERM, U740, Paris, France (F.R., F.B., E.T.-L.); Universit\u00e9 Paris Diderot, Sorbonne Paris Cit\u00e9, G\u00e9n\u00e9tique des Maladies Vasculaires UMR-S740, Paris, France (E.T.-L.); AP-HP,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Kleaveland","sequence":"additional","affiliation":[{"name":"From the Department of Medicine and Cardiovascular Institute (X.Z., A.T.T., W.P., J.Y., M.L.K.), and Department of Pathology (B.K.), University of Pennsylvania, Philadelphia, PA; Department of Pediatric Cardiology, Children's Hospital of Philadelphia, Philadelphia, PA (C.D.M.); Department of G\u00e9n\u00e9tique des Maladies Vasculaires, INSERM, U740, Paris, France (F.R., F.B., E.T.-L.); Universit\u00e9 Paris Diderot, Sorbonne Paris Cit\u00e9, G\u00e9n\u00e9tique des Maladies Vasculaires UMR-S740, Paris, France (E.T.-L.); AP-HP,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Pan","sequence":"additional","affiliation":[{"name":"From the Department of Medicine and Cardiovascular Institute (X.Z., A.T.T., W.P., J.Y., M.L.K.), and Department of Pathology (B.K.), University of Pennsylvania, Philadelphia, PA; Department of Pediatric Cardiology, Children's Hospital of Philadelphia, Philadelphia, PA (C.D.M.); Department of G\u00e9n\u00e9tique des Maladies Vasculaires, INSERM, U740, Paris, France (F.R., F.B., E.T.-L.); Universit\u00e9 Paris Diderot, Sorbonne Paris Cit\u00e9, G\u00e9n\u00e9tique des Maladies Vasculaires UMR-S740, Paris, France (E.T.-L.); AP-HP,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jisheng","family":"Yang","sequence":"additional","affiliation":[{"name":"From the Department of Medicine and Cardiovascular Institute (X.Z., A.T.T., W.P., J.Y., M.L.K.), and Department of Pathology (B.K.), University of Pennsylvania, Philadelphia, PA; Department of Pediatric Cardiology, Children's Hospital of Philadelphia, Philadelphia, PA (C.D.M.); Department of G\u00e9n\u00e9tique des Maladies Vasculaires, INSERM, U740, Paris, France (F.R., F.B., E.T.-L.); Universit\u00e9 Paris Diderot, Sorbonne Paris Cit\u00e9, G\u00e9n\u00e9tique des Maladies Vasculaires UMR-S740, Paris, France (E.T.-L.); AP-HP,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth","family":"Tournier-Lasserve","sequence":"additional","affiliation":[{"name":"From the Department of Medicine and Cardiovascular Institute (X.Z., A.T.T., W.P., J.Y., M.L.K.), and Department of Pathology (B.K.), University of Pennsylvania, Philadelphia, PA; Department of Pediatric Cardiology, Children's Hospital of Philadelphia, Philadelphia, PA (C.D.M.); Department of G\u00e9n\u00e9tique des Maladies Vasculaires, INSERM, U740, Paris, France (F.R., F.B., E.T.-L.); Universit\u00e9 Paris Diderot, Sorbonne Paris Cit\u00e9, G\u00e9n\u00e9tique des Maladies Vasculaires UMR-S740, Paris, France (E.T.-L.); AP-HP,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark L.","family":"Kahn","sequence":"additional","affiliation":[{"name":"From the Department of Medicine and Cardiovascular Institute (X.Z., A.T.T., W.P., J.Y., M.L.K.), and Department of Pathology (B.K.), University of Pennsylvania, Philadelphia, PA; Department of Pediatric Cardiology, Children's Hospital of Philadelphia, Philadelphia, PA (C.D.M.); Department of G\u00e9n\u00e9tique des Maladies Vasculaires, INSERM, U740, Paris, France (F.R., F.B., E.T.-L.); Universit\u00e9 Paris Diderot, Sorbonne Paris Cit\u00e9, G\u00e9n\u00e9tique des Maladies Vasculaires UMR-S740, Paris, France (E.T.-L.); AP-HP,..."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1742-4658.2009.07535.x"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.1918"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.1911"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI39679"},{"key":"e_1_3_3_6_2","first-page":"3129","article-title":"Santa and valentine pattern concentric growth of cardiac myocardium in the zebrafish.","volume":"123","author":"Mably JD","year":"2006","unstructured":"Mably JD, Chuang LP, Serluca FC, Mohideen MA, Chen JN, Fishman MC. Santa and valentine pattern concentric growth of cardiac myocardium in the zebrafish. Development. 2006;123:3129\u20133146.","journal-title":"Development"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI44393"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20110571"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2012.06.004"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20082150"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature09002"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200705175"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20091258"}],"container-title":["Stroke"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/STROKEAHA.114.004809","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T14:44:26Z","timestamp":1715611466000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/STROKEAHA.114.004809"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,5]]},"references-count":12,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2014,5]]}},"alternative-id":["10.1161\/STROKEAHA.114.004809"],"URL":"https:\/\/doi.org\/10.1161\/strokeaha.114.004809","relation":{},"ISSN":["0039-2499","1524-4628"],"issn-type":[{"value":"0039-2499","type":"print"},{"value":"1524-4628","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,5]]},"assertion":[{"value":"2014-01-13","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2014-02-10","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2014-03-18","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}