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Author(s): Helong Zhao [1]; Tara M Mleynek [1]; Dean Y Li (corresponding author) [2] The disruption or malformation of the vascular network can lead to various vascular diseases, such as [...]

Cerebral cavernous malformation (CCM) is a common vascular dysplasia that affects both systemic and central nervous system blood vessels. Loss of function mutations in the CCM2 gene cause CCM. Here we show that targeted disruption of Ccm2 in mice results in failed lumen formation and early embryonic death through an endothelial cell autonomous mechanism. We show that CCM2 regulates endothelial cytoskeletal architecture, cell-to-cell interactions and lumen formation. Heterozygosity at Ccm2, a genotype equivalent to that in human CCM, results in impaired endothelial barrier function. On the basis of our biochemical studies indicating that loss of CCM2 results in activation of RHOA GTPase, we rescued the cellular phenotype and barrier function in heterozygous mice with simvastatin, a drug known to inhibit Rho GTPases. These data offer the prospect for pharmacological treatment of a human vascular dysplasia with a widely available and safe drug., ********** Cerebral cavernous malformations are common vascular malformations that affect the systemic and central nervous system (CNS) vasculature with a prevalence of I in 200 to 250 individuals (1,2) in [...]

The angiogenic sprout has been compared to the growing axon, and indeed, many proteins direct pathfinding by both structures (1). The Roundabout (Robo) proteins are guidance receptors with well-established functions in the nervous system (2,3) however, their role in the mammalian vasculature remains ill defined (4-8). Here we show that an endothelial-specific Robo, Robo4, maintains vascular integrity. Activation of Robo4 by Slit2 inhibits vascular endothelial growth factor (VEGF)-165-induced migration, tube formation and permeability in vitro and VEGF-165-stimulated vascular leak in vivo by blocking Src family kinase activation. In mouse models of retinal and choroidal vascular disease, Slit2 inhibited angiogenesis and vascular leak, whereas deletion of Robo4 enhanced these pathologic processes. Our results define a previously unknown function for Robo receptors in stabilizing the vasculature and suggest that activating Robo4 may have broad therapeutic application in diseases characterized by excessive angiogenesis and/or vascular leak., To ascertain the functional significance of Robo4 in vivo, we generated mice in which exons one through five of the Robo4 locus were replaced with the human placental alkaline phosphatase [...]

A correction to the article "The cerebral cavernous malformation signaling pathway promotes vascular integrity via Rho GTPases" that was published in the April 6, 2009 issue is presented.

A correction to the article "Robo4 stabilizes the vascular network by inhibiting pathologic angiogenesis and endothelial hyperpermeability" that was published in the 2008 issue is presented.