{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T16:12:19Z","timestamp":1791389539126,"version":"4.3.3"},"reference-count":31,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Stroke"],"published-print":{"date-parts":[[2021,4]]},"abstract":"\n Background and Purpose:<\/jats:title>\n \n Cerebral cavernous malformation (CCM) is a common cerebrovascular disease. CCMs are major causes of stroke, cerebral hemorrhage, and neurological deficits in young individuals. Loss-of-function mutations in\n CCM1<\/jats:italic>\n ,\n CCM2<\/jats:italic>\n , and\n CCM3<\/jats:italic>\n have been identified to cause CCM in humans.\n Ccm2-like<\/jats:italic>\n (\n Ccm2l<\/jats:italic>\n ) is a paralog of\n Ccm2<\/jats:italic>\n and is predominantly expressed in endothelial cells (ECs). CCM2L (CCM2-like) competes with CCM2 for binding to CCM1 and has been shown to have an antagonistic function to that of CCM2 during vascular development. The role of CCM2L in CCM pathogenesis is unknown.\n <\/jats:p>\n <\/jats:sec>\n \n Methods:<\/jats:title>\n \n We isolated brain ECs from the inducible-CCM mouse models for gene expression analysis. Micro-computed tomography imaging was used to analyze CCM lesion burden from the genetic cross of\n Ccm2l<\/jats:italic>\n knockout mice (\n Ccm2l<\/jats:italic>\n \u2212\/\u2212<\/jats:sup>\n ) with\n Ccm1<\/jats:italic>\n or\n Ccm2<\/jats:italic>\n -deficient mice to determine the role of\n Ccm2l<\/jats:italic>\n in CCM pathogenesis. Genetic crosses with\n Map3k3<\/jats:italic>\n \n fl\/fl<\/jats:italic>\n <\/jats:sup>\n mice were used to determine the role of\n Map3k3<\/jats:italic>\n in\n Ccm2l<\/jats:italic>\n -facilitated CCM formation.\n <\/jats:p>\n <\/jats:sec>\n \n Results:<\/jats:title>\n \n We demonstrated increased\n Ccm2l<\/jats:italic>\n expression in brain ECs of\n Ccm2<\/jats:italic>\n -deficient mice. Analysis of RNA-seq data from CCM patient samples revealed a trend of increased\n CCM2L<\/jats:italic>\n expression and its positive correlation with Kruppel-like factor 2\/4\n (KLF2\/4<\/jats:italic>\n ) expression. Micro-computed tomography revealed that the deletion of\n Ccm2l<\/jats:italic>\n in\n Ccm2<\/jats:italic>\n -deficient mice increased CCM lesion volume compared with that of controls but had no effect on lesion numbers. Correlating to the increased lesion burden,\n Klf2\/4<\/jats:italic>\n mRNA expressions in brain ECs were significantly increased in double knockouts (\n Ccm2<\/jats:italic>\n - and\n Ccm2l<\/jats:italic>\n -deficient mice) compared with that of controls (\n Ccm2<\/jats:italic>\n deficient). Hemizygous deletion of\n Map3k3<\/jats:italic>\n in ECs relieved CCM lesion burden in the double knockouts. These results suggest that CCM2L regulates the Map3k3-KLF signaling pathway in CCM pathogenesis.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions:<\/jats:title>\n \n Loss of CCM2L aggravates CCM lesion formation in the\n Ccm2<\/jats:italic>\n -deficient mouse model through increased Map3k3-KLF signaling. Our data suggest that increased\n Ccm2l<\/jats:italic>\n expression is a compensatory mechanism in CCM pathogenesis.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1161\/strokeaha.120.031523","type":"journal-article","created":{"date-parts":[[2021,3,4]],"date-time":"2021-03-04T05:06:08Z","timestamp":1614834368000},"page":"1428-1436","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":11,"title":["CCM2L (Cerebral Cavernous Malformation 2 Like) Deletion Aggravates Cerebral Cavernous Malformation Through Map3k3-KLF Signaling Pathway"],"prefix":"10.1161","volume":"52","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0135-8632","authenticated-orcid":true,"given":"Jaesung P.","family":"Choi","sequence":"first","affiliation":[{"name":"Lab of Cardiovascular Signaling, Centenary Institute, Sydney Medical School (J.P.C., X.Z.), University of Sydney, NSW, Australia."},{"name":"Centre for Inflammation, Centenary Institute, School of Life Sciences, University of Technology Sydney, NSW, Australia (J.P.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2386-267X","authenticated-orcid":true,"given":"Xi","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, China (X.Y., X.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuang","family":"He","sequence":"additional","affiliation":[{"name":"Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Beijing, China (S.H., Z.-R.X., C.-R.X.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8228-7281","authenticated-orcid":true,"given":"Renhua","family":"Song","sequence":"additional","affiliation":[{"name":"Epigenetics and RNA Biology Program Centenary Institute, Sydney Medical School (R.S., J.J.-L.W.), University of Sydney, NSW, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zi-Ran","family":"Xu","sequence":"additional","affiliation":[{"name":"Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Beijing, China (S.H., Z.-R.X., C.-R.X.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4077-445X","authenticated-orcid":true,"given":"Matthew","family":"Foley","sequence":"additional","affiliation":[{"name":"Australian Centre for Microscopy and Microanalysis (M.F.), University of Sydney, NSW, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7038-5079","authenticated-orcid":true,"given":"Justin J.-L.","family":"Wong","sequence":"additional","affiliation":[{"name":"Epigenetics and RNA Biology Program Centenary Institute, Sydney Medical School (R.S., J.J.-L.W.), University of Sydney, NSW, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0583-4464","authenticated-orcid":true,"given":"Cheng-Ran","family":"Xu","sequence":"additional","affiliation":[{"name":"Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Beijing, China (S.H., Z.-R.X., C.-R.X.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6277-5168","authenticated-orcid":true,"given":"Xiangjian","family":"Zheng","sequence":"additional","affiliation":[{"name":"Lab of Cardiovascular Signaling, Centenary Institute, Sydney Medical School (J.P.C., X.Z.), University of Sydney, NSW, Australia."},{"name":"Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, China (X.Y., 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