The DOI matches its Crossref record; 54 of the 54 references it cites were found in a registry or an index.
Cerebral cavernous malformations proteins inhibit Rho kinase to stabilize vascular integrity
Open accessAbstract
Endothelial cell–cell junctions regulate vascular permeability, vasculogenesis, and angiogenesis. Familial cerebral cavernous malformations (CCMs) in humans result from mutations of CCM2 (malcavernin, OSM, MGC4607), PDCD10 (CCM3), or KRIT1 (CCM1), a Rap1 effector which stabilizes endothelial cell–cell junctions. Homozygous loss of KRIT1 or CCM2 produces lethal vascular phenotypes in mice and zebrafish. We report that the physical interaction of KRIT1 and CCM2 proteins is required for endothelial cell–cell junctional localization, and lack of either protein destabilizes barrier function by sustaining activity of RhoA and its effector Rho kinase (ROCK). Protein haploinsufficient Krit1+/− or Ccm2+/− mouse endothelial cells manifested increased monolayer permeability in vitro, and both Krit1+/− and Ccm2+/− mice exhibited increased vascular leak in vivo, reversible by fasudil, a ROCK inhibitor. Furthermore, we show that ROCK hyperactivity occurs in sporadic and familial human CCM endothelium as judged by increased phosphorylation of myosin light chain. These data establish that KRIT1–CCM2 interaction regulates vascular barrier function by suppressing Rho/ROCK signaling and that this pathway is dysregulated in human CCM endothelium, and they suggest that fasudil could ameliorate both CCM disease and vascular leak.
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Metadata
- Authors
- Stockton, R. A., Shenkar, R., Awad, I. A., & Ginsberg, M. H.
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2010-03-22
- Volume
- 207
- Issue
- 4
- Pages
- 881-896
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- OpenAlex
- W2171538469
- Cited by
- 351
- References
- 54
- FWCI
- 13.20
- Type
- journal article
- Language
- en
- Open access
- green
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