{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T13:52:53Z","timestamp":1791726773871,"version":"4.3.4"},"reference-count":66,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2024,8,2]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Cerebral vascular malformations (CCMs) are primarily found within the brain, where they result in increased risk for stroke, seizures, and focal neurological deficits. The unique feature of the brain vasculature is the blood-brain barrier formed by the brain neurovascular unit. Recent studies suggest that loss of CCM genes causes disruptions of blood-brain barrier integrity as the inciting events for CCM development. CCM lesions are proposed to be initially derived from a single clonal expansion of a subset of angiogenic venous capillary endothelial cells (ECs) and respective resident endothelial progenitor cells (EPCs). However, the critical signaling events in the subclass of brain ECs\/EPCs for CCM lesion initiation and progression are unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      Brain EC-specific CCM3-deficient (\n                      <jats:italic toggle=\"yes\">Pdcd10<\/jats:italic>\n                      <jats:sup>BECKO<\/jats:sup>\n                      ) mice were generated by crossing\n                      <jats:italic toggle=\"yes\">Pdcd10<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic toggle=\"yes\">fl\/fl<\/jats:italic>\n                      <\/jats:sup>\n                      mice with\n                      <jats:italic toggle=\"yes\">Mfsd2a<\/jats:italic>\n                      -CreER\n                      <jats:sup>T2<\/jats:sup>\n                      mice. Single-cell RNA-sequencing analyses were performed by the chromium single-cell platform (10\u00d7 genomics). Cell clusters were annotated into EC subtypes based on visual inspection and GO analyses. Cerebral vessels were visualized by 2-photon in vivo imaging and tissue immunofluorescence analyses. Regulation of mTOR (mechanistic target of rapamycin) signaling by CCM3 and Cav1 (caveolin-1) was performed by cell biology and biochemical approaches.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      Single-cell RNA-sequencing analyses from P10\n                      <jats:italic toggle=\"yes\">Pdcd1<\/jats:italic>\n                      0\n                      <jats:sup>BECKO<\/jats:sup>\n                      mice harboring visible CCM lesions identified upregulated CCM lesion signature and mitotic EC clusters but decreased blood-brain barrier\u2013associated EC clusters. However, a unique EPC cluster with high expression levels of stem cell markers enriched with mTOR signaling was identified from early stages of the P6\n                      <jats:italic toggle=\"yes\">Pdcd1<\/jats:italic>\n                      0\n                      <jats:sup>BECKO<\/jats:sup>\n                      brain. Indeed, mTOR signaling was upregulated in both mouse and human CCM lesions. Genetic deficiency of Raptor (regulatory-associated protein of mTOR), but not of Rictor (rapamycin-insensitive companion of mTOR), prevented CCM lesion formation in the\n                      <jats:italic toggle=\"yes\">Pdcd10<\/jats:italic>\n                      <jats:sup>BECKO<\/jats:sup>\n                      model. Importantly, the mTORC1 (mTOR complex 1) pharmacological inhibitor rapamycin suppressed EPC proliferation and ameliorated CCM pathogenesis in\n                      <jats:italic toggle=\"yes\">Pdcd10<\/jats:italic>\n                      <jats:sup>BECKO<\/jats:sup>\n                      mice. Mechanistic studies suggested that Cav1\/caveolae increased in CCM3-depleted EPC-mediated intracellular trafficking and complex formation of the mTORC1 signaling proteins.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>CCM3 is critical for maintaining blood-brain barrier integrity and CCM3 loss\u2013induced mTORC1 signaling in brain EPCs initiates and facilitates CCM pathogenesis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.123.324015","type":"journal-article","created":{"date-parts":[[2024,7,3]],"date-time":"2024-07-03T05:00:50Z","timestamp":1719982850000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":24,"title":["mTORC1 Signaling in Brain Endothelial Progenitors Contributes to CCM Pathogenesis"],"prefix":"10.1161","volume":"135","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2479-6096","authenticated-orcid":true,"given":"Wang","family":"Min","sequence":"first","affiliation":[{"name":"Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, Yale University School of Medicine, New Haven, CT (W.M., L.Q., H.Z., N.J., Y.K., V.K.M., M.S., J.H.Z.)."},{"name":"Cardiovascular Medical Center, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China (W.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingfeng","family":"Qin","sequence":"additional","affiliation":[{"name":"Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, Yale University School of Medicine, New Haven, CT (W.M., L.Q., H.Z., N.J., Y.K., V.K.M., M.S., J.H.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9141-7458","authenticated-orcid":true,"given":"Haifeng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, Yale University School of Medicine, New Haven, CT (W.M., L.Q., H.Z., N.J., Y.K., V.K.M., M.S., J.H.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7476-9822","authenticated-orcid":true,"given":"Francesc","family":"L\u00f3pez-Gir\u00e1ldez","sequence":"additional","affiliation":[{"name":"Yale Center for Genomic Analysis, Department of Genetics (F.L.-G.), New Haven, CT."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"Jiang","sequence":"additional","affiliation":[{"name":"Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, Yale University School of Medicine, New Haven, CT (W.M., L.Q., H.Z., N.J., Y.K., V.K.M., M.S., J.H.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9349-1763","authenticated-orcid":true,"given":"Yeaji","family":"Kim","sequence":"additional","affiliation":[{"name":"Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, Yale University School of Medicine, New Haven, CT (W.M., L.Q., H.Z., N.J., Y.K., V.K.M., M.S., J.H.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Varsha K.","family":"Mohan","sequence":"additional","affiliation":[{"name":"Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, Yale University School of Medicine, New Haven, CT (W.M., L.Q., H.Z., N.J., Y.K., V.K.M., M.S., J.H.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3933-2534","authenticated-orcid":true,"given":"Minhong","family":"Su","sequence":"additional","affiliation":[{"name":"Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, Yale University School of Medicine, New Haven, CT (W.M., L.Q., H.Z., N.J., Y.K., V.K.M., M.S., J.H.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4729-423X","authenticated-orcid":true,"given":"Katie N.","family":"Murray","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, Yale University School of Medicine (K.N.M., J.G.), New Haven, CT."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5000-243X","authenticated-orcid":true,"given":"Jaime","family":"Grutzendler","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, Yale University School 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