title: Lack of CCM1 induces hypersprouting and impairs response to flow.
abstract: Cerebral cavernous malformation (CCM) is a disease of vascular malformations known to be caused by mutations in one of three genes: CCM1, CCM2 or CCM3. Despite several studies, the mechanism of CCM lesion onset remains unclear. Using a Ccm1 knockout mouse model, we studied the morphogenesis of early lesion formation in the retina in order to provide insight into potential mechanisms. We demonstrate that lesions develop in a stereotypic location and pattern, preceded by endothelial hypersprouting as confirmed in a zebrafish model of disease. The vascular defects seen with loss of Ccm1 suggest a defect in endothelial flow response. Taken together, these results suggest new mechanisms of early CCM disease pathogenesis and provide a framework for further study.
authors.affiliation: Department of Molecular Medicine, Department of Oncological Sciences.
authors.forename: Tara M
authors.initials: TM
authors.lastname: Mleynek
authors.affiliation: Department of Molecular Medicine, Department of Oncological Sciences.
authors.forename: Aubrey C
authors.initials: AC
authors.lastname: Chan
authors.affiliation: Flourescence Imaging Core.
authors.forename: Michael
authors.initials: M
authors.lastname: Redd
authors.affiliation: Department of Molecular Medicine, Department of Bioengineering.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Gibson
authors.affiliation: Department of Molecular Medicine, Department of Human Genetics.
authors.forename: Chadwick T
authors.initials: CT
authors.lastname: Davis
authors.affiliation: Department of Molecular Medicine, Department of Human Genetics.
authors.forename: Dallas S
authors.initials: DS
authors.lastname: Shi
authors.affiliation: Department of Molecular Medicine, Small Animal Ultrasound Core, University of Utah, Salt Lake City 84112, USA.
authors.forename: Tiehua
authors.initials: T
authors.lastname: Chen
authors.affiliation: Department of Molecular Medicine, Small Animal Ultrasound Core, University of Utah, Salt Lake City 84112, USA.
authors.forename: Kandis L
authors.initials: KL
authors.lastname: Carter
authors.affiliation: Department of Molecular Medicine.
authors.forename: Jing
authors.initials: J
authors.lastname: Ling
authors.affiliation: Vascular Biology Laboratory, London Research Institute, Cancer Research UK, London WC2A 3LY, UK.
authors.forename: Raquel
authors.initials: R
authors.lastname: Blanco
authors.affiliation: Vascular Patterning Laboratory, VIB3-Vesalius Research Center and CMVB, Department of Oncology, KU Leuven Campus Gasthuisberg O&N4, Herestraat 49 box 912, Leuven B-3000, Belgium.
authors.forename: Holger
authors.initials: H
authors.lastname: Gerhardt
authors.affiliation: Department of Molecular Medicine, Small Animal Ultrasound Core, University of Utah, Salt Lake City 84112, USA, Division of Cardiovascular Medicine, Salt Lake City 84132, USA and.
authors.forename: Kevin
authors.initials: K
authors.lastname: Whitehead
authors.affiliation: Department of Molecular Medicine, Department of Oncological Sciences, Division of Cardiovascular Medicine, Salt Lake City 84132, USA and The Key Laboratory for Human Disease Gene Study of Sichuan Province, Institute of Laboratory Medicine, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, China dean.li@u2m2.utah.edu kevin.whitehead@u2m2.utah.edu.
authors.forename: Dean Y
authors.initials: DY
authors.lastname: Li
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D020786:Hemangioma, Cavernous, Central Nervous System / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D000075927:KRIT1 Protein; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D012160:Retina / Q000473:pathology*; D015027:Zebrafish
chemical_list: D000075927:KRIT1 Protein; C491535:Krit1 protein, mouse; D008869:Microtubule-Associated Proteins; D011518:Proto-Oncogene Proteins