Editors' ChoiceCerebral Cavernous Malformation Disease

Too Much ROCK Is Bad for the Brain

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Science Translational Medicine  12 May 2010:
Vol. 2, Issue 31, pp. 31ec75
DOI: 10.1126/scitranslmed.3001253

Familial cerebral cavernous malformations (CCM) disease, a vascular disorder, can remain asymptomatic or lead to severe symptoms. The associated lesions consist of collections of small vessel dilations (outpouchings) with weak endothelial layers and ineffective connections between cells. When these lesions occur in the brain, they predispose to neurological impairment, seizures, and stroke. CCM disease results from mutations in the CCM1 (KRIT1), CCM2, or CCM3 genes, but the biochemical roles of the encoded proteins have been unclear. Now, Stockton et al. shed new light on the function of KRIT1 and CCM2.

Previous work from this group showed that depletion of KRIT1 from endothelial cells increases the permeabilty of the cell monolayer and leads to the formation of actin stress fibers, suggesting that KRIT1 might suppress signaling by RhoA, a small guanosine triphosphatase that regulates the formation of such fibers. In the present study, the researchers observed that depletion of KRIT1 in human umbilical vein endothelial cells leads to an increase in activated RhoA, showing that KRIT1 inhibits RhoA activity. Inhibitors of ROCK, a RhoA-activated kinase that phosphorylates the myosin light chain, reversed the effects of KRIT1 depletion. Mice with reduced KRIT1 or CCM2 levels display increased blood vessel leakiness. This dysfunction was reversed by fasudil, a ROCK inhibitor, suggesting a possible therapeutic application of this compound, already in clinical use, for CCM disease. The authors also showed that human CCM lesions display increased phosphorylation of myosin light chain, reflecting abnormal blood vessel RhoA-ROCK signaling. Further experiments in cell culture showed that a physical interaction between KRIT1 and CCM2 is needed to suppress ROCK activity.

These findings elegantly illustrate how investigations in cultured cells can inform the work done in animals that in turn can enable us to gain insight into mechanisms of human disease, as well as into potential therapeutic approaches.

R. A. Stockton et al., Cerebral cavernous malformations proteins inhibit Rho kinase to stabilize vascular integrity. J. Exp. Med. 207, 881–896 (2010). [Abstract]

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