{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T10:05:37Z","timestamp":1790935537052,"version":"4.1.0"},"reference-count":36,"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":[[2025,4]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>\n                      Cerebral cavernous malformations (CCMs) refer to vascular dysplasia primarily found in the brain, affecting \u22480.5% of the population. A somatic\n                      <jats:italic>Map3k3<\/jats:italic>\n                      <jats:sup>I441M<\/jats:sup>\n                      mutation has been found in \u224840% of patients with sporadic CCMs, which were typically accompanied by somatic gain-of-function mutations in\n                      <jats:italic>PIK3CA<\/jats:italic>\n                      . Although mouse models of adeno-associated virus-BR1\u2013mediated mutant overexpression have been reported, these models have limitations in representing clinical specimens of CCMs, which typically harbor single allele mutation in\n                      <jats:italic>Map3k3<\/jats:italic>\n                      . A\n                      <jats:italic>Map3k3<\/jats:italic>\n                      <jats:sup>I441M<\/jats:sup>\n                      knock-in murine model of CCMs has not yet been established.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      The\n                      <jats:italic>Map3k3<\/jats:italic>\n                      <jats:sup>I441M<\/jats:sup>\n                      knock-in mice were crossed with\n                      <jats:italic>Cdh5<\/jats:italic>\n                      -creER\n                      <jats:sup>T2<\/jats:sup>\n                      mice to induce mutant gene expression specifically in endothelial cells. Subsequently,\n                      <jats:italic>Map3k3<\/jats:italic>\n                      <jats:sup>I441M<\/jats:sup>\n                      mice were bred with\n                      <jats:italic>Pten<\/jats:italic>\n                      <jats:sup>fl\/fl<\/jats:sup>\n                      mice to generate\n                      <jats:italic>Map3k3<\/jats:italic>\n                      <jats:sup>I441M<\/jats:sup>\n                      ;\n                      <jats:italic>Pten<\/jats:italic>\n                      <jats:sup>fl\/fl<\/jats:sup>\n                      mice. In both murine models, CCM lesions were examined using magnetic resonance imaging, while single-cell RNA sequencing and immunostaining were utilized to investigate the pathomechanism of the mutation. Finally, we administered an mTOR (mechanistic target of rapamycin) inhibitor to explore its therapeutic effect on lesions of both murine models.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      Both endothelial\n                      <jats:italic>Map3k3<\/jats:italic>\n                      <jats:sup>I441M<\/jats:sup>\n                      mutant juvenile mice and\n                      <jats:italic>Map3k3<\/jats:italic>\n                      <jats:sup>I441M<\/jats:sup>\n                      ;\n                      <jats:italic>Pten<\/jats:italic>\n                      <jats:sup>fl\/fl<\/jats:sup>\n                      mice developed abnormal lesions with human CCM characteristics. In\n                      <jats:italic>Map3k3<\/jats:italic>\n                      <jats:sup>I441M<\/jats:sup>\n                      mice, the mutant promoted endothelial apoptosis, while activation of the PI3K (phosphatidylinositol 3-kinase) pathway was able to activate the downstream AKT (protein kinase B)\/mTOR\/p-S6 (phosphorylated S6 ribosomal protein) pathway and upregulate VEGFA (vascular endothelial growth factor A) expression, counteracting apoptosis, and facilitating lesion progression. The activation of PI3K signaling is required for\n                      <jats:italic>Map3k3<\/jats:italic>\n                      <jats:sup>I441M<\/jats:sup>\n                      to generate CCM-like lesions in adult mice. Finally, we demonstrated that rapamycin effectively inhibited the formation of lesions in the\n                      <jats:italic>Map3k3<\/jats:italic>\n                      <jats:sup>I441M<\/jats:sup>\n                      mice and\n                      <jats:italic>Map3k3<\/jats:italic>\n                      <jats:sup>I441M<\/jats:sup>\n                      ;\n                      <jats:italic>Pten<\/jats:italic>\n                      <jats:sup>fl\/fl<\/jats:sup>\n                      mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>\n                      <jats:italic>Map3k3<\/jats:italic>\n                      <jats:sup>I441M<\/jats:sup>\n                      heterozygous is sufficient to induce lesions in juvenile mice, while the additional activation of PI3K signaling is required for the effective formation of CCMs at the adult stage. The\n                      <jats:italic>Map3k3<\/jats:italic>\n                      <jats:sup>I441M<\/jats:sup>\n                      murine model provides a preclinical model for further mechanistic and therapeutic studies of CCMs.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/strokeaha.124.049935","type":"journal-article","created":{"date-parts":[[2025,3,24]],"date-time":"2025-03-24T14:08:48Z","timestamp":1742825328000},"page":"1010-1025","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":11,"title":["<i>Map3k3\u2009<\/i>\n                    <sup>I441M<\/sup>\n                    Knock-In Mouse Model of Cerebral Cavernous Malformations"],"prefix":"10.1161","volume":"56","author":[{"given":"Hongyuan","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, Beijing Tiantan Hospital (H.X., R.H., S.Z., Y.S., Jie Wang, Q.H., Q.Y., J.T., Y.J., Y.C.), Capital Medical University, China."},{"name":"China National Clinical Research Center for Neurological Diseases, Beijing (H.X., R.H., S.Z., Y.S., Jie Wang, Q.H., Q.Y., J.T., Y.J., Y.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingxi","family":"Yang","sequence":"additional","affiliation":[{"name":"Division of Life Science, Department of Chemical and Biological Engineering, and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, China (Y.Y., Q.Z., Jiguang Wang)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiuxia","family":"Zhou","sequence":"additional","affiliation":[{"name":"Division of Life Science, Department of Chemical and Biological Engineering, and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, China (Y.Y., Q.Z., Jiguang 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