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PMID:20926893

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Citation

Liu, H, Rigamonti, D, Badr, A and Zhang, J (2011) Ccm1 regulates microvascular morphogenesis during angiogenesis. J. Vasc. Res. 48:130-40

Abstract

Cerebral cavernous malformations (CCMs) are characterized by abnormally dilated intracranial capillaries that have a propensity to bleed. The development of some CCMs in humans has been attributed to mutations in CCM1 and CCM2 genes. In animal models, major cardiovascular defects caused by both gene mutations have been observed. However, the effects of the loss of Ccm function on the microvasculature in animal models are less defined. Using high-resolution imaging in vivo, we demonstrated that the loss of Ccm1 in zebrafish embryos leads to failed microvascular lumenization during angiogenesis due to impaired intraendothelial vacuole formation and fusion. No developmental changes during vasculogenesis and the initial stage of angiogenesis were observed, being in contrast to prior reports. In vivo zebrafish studies were further substantiated by in vitro findings in human endothelial cells that elucidated the biochemical pathways of CCM1 deficiency. We found that CCM1 regulates angiogenic microvascular lumen formation through Rac1 small GTPase. In summary, Ccm1 has been identified as a key angiogenic modulator in microvascular tubulogenesis. Additionally, the microvascular pathology observed in developing Ccm1 mutant zebrafish embryos mirrors that seen in human CCM lesions, suggesting that zebrafish might provide a superior animal model to study the pathogenesis of human CCM.

Links

PubMed PMC3219476 Online version:10.1159/000316851

Keywords

Animals; Cell Line; Disease Models, Animal; Embryo, Nonmammalian/blood supply; Embryo, Nonmammalian/metabolism; Endothelial Cells/cytology; Endothelial Cells/metabolism; Gene Expression Regulation, Developmental/genetics; Hemangioma, Cavernous, Central Nervous System/genetics; Hemangioma, Cavernous, Central Nervous System/metabolism; Humans; Microtubule-Associated Proteins/genetics; Microtubule-Associated Proteins/metabolism; Microvessels/embryology; Microvessels/metabolism; Morphogenesis/genetics; Mutation; Neovascularization, Physiologic/genetics; Zebrafish; Zebrafish Proteins/genetics; Zebrafish Proteins/metabolism; rac1 GTP-Binding Protein/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

DANRE:KRIT1

involved_in

GO:0001525: angiogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-GENO-110118-2

P

Seeded From UniProt

complete

DANRE:KRIT1

involved_in

GO:0007033: vacuole organization

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-GENO-110118-2

P

Seeded From UniProt

complete

DANRE:KRIT1

involved_in

GO:0072554: blood vessel lumenization

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-GENO-110118-2

P

Seeded From UniProt

complete


See also

References

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