{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T01:18:26Z","timestamp":1790039906585,"version":"4.0.1"},"reference-count":131,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2022,4,30]],"date-time":"2022-04-30T00:00:00Z","timestamp":1651276800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH Early Stage Training in the Neurosciences Training","award":["T32-NS076401"],"award-info":[{"award-number":["T32-NS076401"]}]},{"name":"NIH Early Stage Training in the Neurosciences Training","award":["R21-NS111205"],"award-info":[{"award-number":["R21-NS111205"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cerebral cavernous malformation (CCM) is a cerebromicrovascular disease that affects up to 0.5% of the population. Vessel dilation, decreased endothelial cell\u2013cell contact, and loss of junctional complexes lead to loss of brain endothelial barrier integrity and hemorrhagic lesion formation. Leakage of hemorrhagic lesions results in patient symptoms and complications, including seizures, epilepsy, focal headaches, and hemorrhagic stroke. CCMs are classified as sporadic (sCCM) or familial (fCCM), associated with loss-of-function mutations in KRIT1\/CCM1, CCM2, and PDCD10\/CCM3. Identifying the CCM proteins has thrust the field forward by (1) revealing cellular processes and signaling pathways underlying fCCM pathogenesis, and (2) facilitating the development of animal models to study CCM protein function. CCM animal models range from various murine models to zebrafish models, with each model providing unique insights into CCM lesion development and progression. Additionally, these animal models serve as preclinical models to study therapeutic options for CCM treatment. This review briefly summarizes CCM disease pathology and the molecular functions of the CCM proteins, followed by an in-depth discussion of animal models used to study CCM pathogenesis and developing therapeutics.<\/jats:p>","DOI":"10.3390\/ijms23095000","type":"journal-article","created":{"date-parts":[[2022,5,1]],"date-time":"2022-05-01T06:23:08Z","timestamp":1651386188000},"page":"5000","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Cerebral Cavernous Malformation Pathogenesis: Investigating Lesion Formation and Progression with Animal Models"],"prefix":"10.3390","volume":"23","author":[{"given":"Chelsea M.","family":"Phillips","sequence":"first","affiliation":[{"name":"Neuroscience Graduate Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Svetlana M.","family":"Stamatovic","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6441-5334","authenticated-orcid":false,"given":"Richard F.","family":"Keep","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA"},{"name":"Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anuska V.","family":"Andjelkovic","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA"},{"name":"Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,4,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1038\/nrneurol.2009.177","article-title":"Cavernous malformations: Natural history, diagnosis and treatment","volume":"5","author":"Batra","year":"2009","journal-title":"Nat. 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