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Regulation of cardiovascular development and integrity by the heart of glass–cerebral cavernous malformation protein pathway
Open accessAbstract
Cerebral cavernous malformations (CCMs) are human vascular malformations caused by mutations in three genes of unknown function: KRIT1, CCM2 and PDCD10. Here we show that the heart of glass (HEG1) receptor, which in zebrafish has been linked to ccm gene function, is selectively expressed in endothelial cells. Heg1−/− mice showed defective integrity of the heart, blood vessels and lymphatic vessels. Heg1−/−; Ccm2lacZ/+ and Ccm2lacZ/lacZ mice had more severe cardiovascular defects and died early in development owing to a failure of nascent endothelial cells to associate into patent vessels. This endothelial cell phenotype was shared by zebrafish embryos deficient in heg, krit1 or ccm2 and reproduced in CCM2-deficient human endothelial cells in vitro. Defects in the hearts of zebrafish lacking heg or ccm2, in the aortas of early mouse embryos lacking CCM2 and in the lymphatic vessels of neonatal mice lacking HEG1 were associated with abnormal endothelial cell junctions like those observed in human CCMs. Biochemical and cellular imaging analyses identified a cell-autonomous pathway in which the HEG1 receptor couples to KRIT1 at these cell junctions. This study identifies HEG1-CCM protein signaling as a crucial regulator of heart and vessel formation and integrity.
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Cited by
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Kikuchi, K., Holdway, J. E., Major, R. J., Blum, N., Dahn, R. D., Begemann, G., & Poss, K. D. (2011) · Developmental Cell · doi:10.1016/j.devcel.2011.01.010 · Cited by 461
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Biology of Vascular Malformations of the Brain
Leblanc, G. G., Golanov, E., Awad, I. A., Young, W. L., & Collaborators, B. O. V. M. O. T. B. N. W. (2009) · Stroke · doi:10.1161/strokeaha.109.563692 · Cited by 262
Cerebral cavernous malformations: from CCM genes to endothelial cell homeostasis
Fischer, A., Zalvide, J., Faurobert, E., Albiges-Rizo, C., & Tournier-Lasserve, E. (2013) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2013.02.004 · Cited by 199
Metadata
- Authors
- Kleaveland, B., Zheng, X., Liu, J. J., Blum, Y., Tung, J. J., Zou, Z., Sweeney, S. M., Chen, M., Guo, L., Lu, M.-M., Zhou, D., Kitajewski, J., Affolter, M., Ginsberg, M. H., & Kahn, M. L.
- Venue
- Nature Medicine
- Published
- 2009-01-18
- Volume
- 15
- Issue
- 2
- Pages
- 169-176
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2094722906
- Cited by
- 248
- References
- 0
- FWCI
- 13.88
- Type
- journal article
- Language
- en
- Open access
- green
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- Kleaveland, B., Zheng, X., Liu, J. J., Blum, Y., Tung, J. J., Zou, Z., Sweeney, S. M., Chen, M., Guo, L., Lu, M.-M., Zhou, D., Kitajewski, J., Affolter, M., Ginsberg, M. H., & Kahn, M. L. (2009). Regulation of cardiovascular development and integrity by the heart of glass–cerebral cavernous malformation protein pathway. Nature Medicine. https://doi.org/10.1038/nm.1918
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