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Hum Mol Genet. 2014 Dec 1;23(23):6223-34. doi: 10.1093/hmg/ddu342. Epub 2014 Jul 2.

Lack of CCM1 induces hypersprouting and impairs response to flow.

Author information

1
Department of Molecular Medicine, Department of Oncological Sciences.
2
Flourescence Imaging Core.
3
Department of Molecular Medicine, Department of Bioengineering.
4
Department of Molecular Medicine, Department of Human Genetics.
5
Department of Molecular Medicine, Small Animal Ultrasound Core, University of Utah, Salt Lake City 84112, USA.
6
Department of Molecular Medicine.
7
Vascular Biology Laboratory, London Research Institute, Cancer Research UK, London WC2A 3LY, UK.
8
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.
9
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.
10
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.

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.

PMID:
24990152
PMCID:
PMC4222362
DOI:
10.1093/hmg/ddu342
[Indexed for MEDLINE]
Free PMC Article

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